2024年12月3日 (二) 17:31的最后版本

神经系统的突触传递

本页英文内容取自：经典教材医学生理学（第三版） (Medical Physiology, 3rd Edtion, Walter F Boron, published in 2016)

中文内容由 BH1RBH (Jack Tan) 粗糙翻译

蓝色 【注】 后内容为 BH1RBH (Jack Tan) 所加之注释

After meticulous study of spinal reflexes, Charles Sherrington N10-2 deduced that neurons somehow communicate information, one to the next, by a mechanism that is fundamentally different from the way that they conduct signals along their axons. Sherrington had merged his physiological conclusions with the anatomical observations (Fig. 13-1) of his contemporary, the preeminent neuroanatomist Santiago Ramón y Cajal. N10-1 Ramón y Cajal had proposed that neurons are distinct entities, fundamental units of the nervous system that are discontinuous with each other. Discontinuous neurons must nevertheless communicate, and Sherrington in 1897 proposed that the synapse, a specialized apposition between cells, mediates the signals. The word synapse implies “contiguity, not continuity” between neurons, as Ramón y Cajal himself explained it. When the fine structure of synapses was finally revealed with the electron microscope in the 1950s, the vision of Ramón y Cajal and Sherrington was amply sustained. Neurons come very close together at chemical synapses (see p. 206), but their membranes and cytoplasm remain distinct. At electrical synapses (see p. 205), which are less common than chemical synapses, the membranes remain distinct, but ions and other small solutes can diffuse through the gap junctions, a form of continuity.

在对脊髓反射进行细致的研究后，Charles Sherrington [N10-2] 推断出神经元以某种方式将信息从一个传递到另一个，这种机制与它们沿轴突传导信号的方式根本不同。Sherrington 将他的生理学结论与他同时代杰出的神经解剖学家 Santiago Ramón y Cajal 的解剖观察（图 13-1）相结合[N10-1]Ramón y Cajal 提出神经元是不同的实体，是神经系统的基本单位，彼此不连续。然而，不连续的神经元必须进行交流，Sherrington 在 1897 年提出突触，即细胞之间的特殊并置，介导信号。突触这个词意味着神经元之间的“毗连性，而不是连续性”，正如 Ramón y Cajal 本人所解释的那样。当电子显微镜最终在 1950 年代揭示突触的精细结构时，Ramón y Cajal 和 Sherrington 的愿景得到了充分的支持。神经元在化学突触处非常靠近（见第 206 页），但它们的膜和细胞质仍然不同。在电突触（见第 205 页）处，比化学突触更不常见，膜保持清晰，但离子和其他小溶质可以通过间隙连接扩散，这是一种连续性形式。

[编辑] 1 Neuronal Synapses（神经元突触）

[编辑] 1.1 神经元突触的分子机制与神经肌肉接头的分子机制相似但不相同

The molecular mechanisms of neuronal synapses are similar but not identical to those of the neuromuscular junction

Chemical synapses use diffusible transmitter molecules to communicate messages between two cells. The first chemical synapse to be understood in detail was the neuromuscular junction (the nerve-muscle synapse) in vertebrate skeletal muscle, which is described in Chapter 8. In this chapter, we are concerned with the properties of the synapses that occur between neurons. We now know that all synapses share certain basic biochemical and physiological mechanisms, and thus many basic insights gained from the neuromuscular junction are also applicable to synapses in the brain. However, neuronal synapses differ from neuromuscular junctions in many important ways; they also differ widely among themselves, and it is the diverse properties of synapses that help make each part of the brain unique.

化学突触使用可扩散的递质分子在两个细胞之间传递信息。第一个需要详细理解的化学突触是脊椎动物骨骼肌中的神经肌肉接头（神经肌肉突触），这在第 8 章中进行了描述。在本章中，我们关注神经元之间发生的突触的特性。我们现在知道所有突触都有某些基本的生化和生理机制，因此从神经肌肉接头获得的许多基本见解也适用于大脑中的突触。然而，神经元突触在许多重要方面与神经肌肉接头不同；它们之间也有很大差异，正是突触的不同特性有助于使大脑的每个部分都独一无二。

It is useful to begin by reviewing some of the mechanisms that are common to all chemical synapses (see Figs. 8-2 and 8-3). N13-1 Synaptic transmission at chemical synapses occurs in seven steps:

首先回顾所有化学突触共有的一些机制是有用的（见图 8-2 和 8-3）。N13-1 化学突触的突触传递分为七个步骤：

Step 1: Neurotransmitter molecules are packaged into membranous vesicles, and the vesicles are concentrated and docked at the presynaptic terminal.

第 1 步：神经递质分子被包装成膜囊泡，囊泡浓缩并停靠在突触前末梢。

Step 2: The presynaptic membrane depolarizes, usually as the result of an action potential, although some synapses respond to graded variations of membrane potential (Vm).

第 2 步：突触前膜去极化，通常是动作电位的结果，尽管一些突触对膜电位 (Vm) 的分级变化做出反应。

Step 3: The depolarization causes voltage-gated Ca2+ channels to open and allows Ca2+ ions to flow into the terminal.

第 3 步：去极化导致电压门控 Ca2+ 通道打开，并允许 Ca2+ 离子流入端子。

Step 4: The resulting increase in intracellular [Ca2+] triggers fusion of vesicles with the presynaptic membrane (see pp. 219–221), and the rate of transmitter release increases ~100,000-fold above baseline. The Ca2+ dependence of fusion is conferred by neuron-specific protein components of the fusion apparatus called synaptotagmins. The actual fusion events are incredibly fast; each individual exocytosis requires only a fraction of a millisecond to be completed.

第 4 步：细胞内 [Ca2+] 的增加触发囊泡与突触前膜的融合（参见第 219-221 页），递质释放速率比基线增加 ~100,000 倍。融合的 Ca2+ 依赖性是由融合装置的神经元特异性蛋白质成分（称为突触结合蛋白）赋予的。实际的融合事件非常快;每个单独的胞吐作用只需要几分之一毫秒即可完成。

Step 5: The transmitter is released into the extracellular space in quantized amounts and diffuses passively across the synaptic cleft.

第 5 步：递质以量化量释放到细胞外间隙中，并被动地扩散穿过突触间隙。

Step 6: Some of the transmitter molecules bind to receptors in the postsynaptic membrane, and the activated receptors trigger some postsynaptic event, usually the opening of an ion channel or the activation of a G protein–coupled signal cascade.

第 6 步：一些递质分子与突触后膜中的受体结合，激活的受体触发一些突触后事件，通常是离子通道的打开或 G 蛋白偶联信号级联的激活。

Step 7: Transmitter molecules diffuse away from postsynaptic receptors and are eventually cleared away by continued diffusion, enzymatic degradation, or active uptake into cells. In addition, the presynaptic machinery retrieves the membrane of the exocytosed synaptic vesicle, perhaps by endocytosis from the cell surface.

第 7 步：递质分子从突触后受体扩散出去，最终通过持续扩散、酶降解或主动摄取到细胞中清除。此外，突触前机制可能通过细胞表面的内吞作用取回胞吐作用突触囊泡的膜。

The molecular machinery of synapses is closely related to components that are universal in eukaryotic cells (see p. 37). A large set of proteins is involved in the docking and fusion of vesicles, and the proteins present in nerve terminals are remarkably similar to the ones mediating fusion and secretion in yeast. Docking and fusion of synaptic vesicles are discussed on page 219. Ligand-gated ion channels and G protein–coupled receptors (GPCRs), the receptors on the postsynaptic membrane, are also present in all eukaryotic cells and mediate processes as disparate as the recognition of nutrients and poisons, and the identification of other members of the species. Even most of the neurotransmitters themselves are simple molecules, identical or very similar to those used in general cellular metabolism. Clearly, the evolutionary roots of synaptic transmission are much older than nervous systems themselves.

突触的分子机制与真核细胞中普遍存在的成分密切相关（见第 37 页）。大量蛋白质参与囊泡的对接和融合，存在于神经末梢的蛋白质与酵母中介导融合和分泌的蛋白质非常相似。突触小泡的对接和融合在第 219 页讨论。配体门控离子通道和 G 蛋白偶联受体 （GPCR） 是突触后膜上的受体，也存在于所有真核细胞中，并介导与识别营养物质和毒物以及识别该物种的其他成员一样不同的过程。甚至大多数神经递质本身也是简单的分子，与一般细胞代谢中使用的分子相同或非常相似。显然，突触传递的进化根源比神经系统本身要古老得多。

Within nervous systems, however, myriad variations on the basic molecular building blocks yield synapses with wide-ranging properties. Neuronal synapses vary widely in the size of the synaptic contact, the identity of the neurotransmitter, the nature of the postsynaptic receptors, the efficiency of synaptic transmission, the mechanism used for terminating transmitter action, and the degree and modes of synaptic plasticity. Thus, the properties of neuronal synapses can be tuned to achieve the diverse functions of the brain.

然而，在神经系统中，基本分子构建单元的无数变化会产生具有广泛特性的突触。神经元突触在突触接触的大小、神经递质的身份、突触后受体的性质、突触传递的效率、用于终止递质作用的机制以及突触可塑性的程度和模式方面差异很大。因此，可以调整神经元突触的特性以实现大脑的各种功能。

A major difference between the neuromuscular junction and most neuronal synapses is the type of neurotransmitter used. All skeletal neuromuscular junctions use acetylcholine (ACh). In contrast, neuronal synapses use many transmitters. The most ubiquitous are amino acids: glutamate and aspartate excite, whereas gamma-aminobutyric acid (GABA) and glycine inhibit. Other transmitters include simple amines, such as ACh, norepinephrine, serotonin, and histamine, ubiquitous molecules such as ATP and adenosine, and a wide array of peptides.

神经肌肉接头和大多数神经元突触之间的一个主要区别是所使用的神经递质类型。所有骨骼神经肌肉接头都使用乙酰胆碱 （ACh）。相比之下，神经元突触使用许多递质。最普遍的是氨基酸：谷氨酸和天冬氨酸兴奋，而 γ-氨基丁酸 （GABA） 和甘氨酸则具有抑制作用。其他递质包括简单的胺，如 ACh、去甲肾上腺素、血清素和组胺，普遍存在的分子，如 ATP 和腺苷，以及多种肽。

Even more varied than the neuronal transmitters are their receptors. Whereas skeletal muscle manufactures a few modest variants of its ACh receptors, the nervous system typically has several major receptor variants for each neurotransmitter. Knowledge about the wide range of transmitters and receptors is essential to understand the chemical activity of the brain as well as the drugs that influence brain activity. For one thing, the many transmitter systems in the brain generate responses with widely varying durations that range from a few milliseconds to days (Fig. 13-2).

比神经元递质更多样化的是它们的受体。骨骼肌产生一些适度的 ACh 受体变体，而神经系统通常为每种神经递质提供几种主要的受体变体。了解各种递质和受体对于了解大脑的化学活动以及影响大脑活动的药物至关重要。首先，大脑中的许多发射器系统产生的反应持续时间差异很大，从几毫秒到几天不等（图 13-2）。

[编辑] 1.2 突触前末梢可能接触树突、体细胞或轴突处的神经元，并且可能包含透明囊泡和致密核心颗粒

Presynaptic terminals may contact neurons at the dendrite, soma, or axon and may contain both clear vesicles and dense-core granules

Chemical synapses between neurons are generally small, often <1 μm in diameter, which means that their detailed structure can be seen only with an electron microscope (Fig. 13-3); under the light microscope, brain synapses are usually visible only as swellings along or at the termination of the axons (see Fig. 13-1). These swellings are actually the silhouettes of the bouton terminals—the presynaptic terminals. Most presynaptic terminals arise from axons, and they can form synapses on virtually any part of a neuron. The contact site and direction of communication determine the way in which a synapse is named: axodendritic, axosomatic, and axoaxonic synapses (Fig. 13-4). These synapses are the most common types in the nervous system. In many cases, synapses occur on small outpockets of the dendritic membrane called spines and are termed axospinous synapses. However, not all synapses arise from axons, and dendrodendritic, somatosomatic, and even somatodendritic synapses may be found in the mammalian brain.

神经元之间的化学突触通常很小，直径通常为 <1 μm，这意味着它们的详细结构只能用电子显微镜看到（图 13-3）；在光学显微镜下，脑突触通常只能看到沿轴突或轴突末端的肿胀（见图 13-1）。这些肿胀实际上是钮扣末梢的轮廓——突触前末梢。大多数突触前末梢起源于轴突，它们几乎可以在神经元的任何部分形成突触。接触部位和通信方向决定了突触的命名方式：轴突突触、轴突突触和轴突突触（图 13-4）。这些突触是神经系统中最常见的类型。在许多情况下，突触发生在树突状膜的小外袋上，称为轴棘突触。然而，并非所有突触都起源于轴突，树突突、体体甚至体突突可能在哺乳动物的大脑中发现。

Despite their differences in size, site, and shape, all synapses share one basic function: they deliver a small amount of chemical transmitter onto a circumscribed patch of postsynaptic membrane. To accomplish this task, they use certain common anatomical features, most of them familiar from discussions of the neuromuscular junction (see Chapter 8).

尽管它们的大小、位置和形状不同，但所有突触都有一个基本功能：它们将少量化学递质输送到突触后膜的限定斑块上。为了完成这项任务，他们使用了某些常见的解剖特征，其中大多数在神经肌肉接头的讨论中很熟悉（见第 8 章）。

Synapses are polarized, which means that their two apposed sides have different structures. This polarity reflects the fact that most synapses transmit information primarily in one direction, although retrograde transmission also occurs in many synapses in one direction but not in the other (we will see that some rare exceptions do exist). The presynaptic side contains numerous clear vesicles, 40 to 50 nm in diameter, that appear empty when viewed by transmission electron microscopy. Synaptic termini may also contain large (100 to 200 nm in diameter) dense-core secretory granules that are morphologically quite similar to the secretory granules of endocrine cells. These granules contain neuropeptides; that is, peptides or small proteins that act as neurotransmitters and for which receptors exist in the postsynaptic membranes. Many of these neuropeptides are identical to substances secreted by “traditional” endocrine cells. Endocrine hormones such as adrenocorticotropic hormone, vasoactive intestinal peptide, and cholecystokinin are found in dense-core secretory granules present in the terminals of certain central and peripheral neurons.

突触是极化的，这意味着它们的两个并置侧具有不同的结构。这种极性反映了大多数突触主要在一个方向上传递信息的事实，尽管逆行传递也发生在一个方向的许多突触中，但不发生在另一个方向上（我们将看到确实存在一些罕见的例外）。突触前侧包含许多直径为 40 至 50 nm 的透明囊泡，通过透射电子显微镜观察时看起来是空的。突触末端也可能包含大的（直径为 100 至 200 nm）致密核心分泌颗粒，其形态与内分泌细胞的分泌颗粒非常相似。这些颗粒含有神经肽;也就是说，充当神经递质的肽或小蛋白，其受体存在于突触后膜中。这些神经肽中的许多与 “传统” 内分泌细胞分泌的物质相同。内分泌激素，如促肾上腺皮质激素、血管活性肠肽和胆囊收缩素，存在于某些中枢和外周神经元末端的致密核心分泌颗粒中。

The clear synaptic vesicles (i.e., not the dense-core granules) are anchored and shifted about by a dense network of cytoskeletal proteins. Some vesicles are clustered close to the part of the presynaptic membrane that apposes the synaptic contact; these vesicle attachment sites are called active zones. Synaptic vesicles are lined up several deep along the active zones, which are the regions of actual exocytosis. The number of active zones per synapse varies greatly (active zones are marked with arrows in the synapses in Fig. 13-3). Most synapses in the central nervous system (CNS) have relatively few active zones, often only 1 but occasionally as many as 10 or 20 (versus the hundreds in the neuromuscular junction). If we could view the presynaptic face of an active zone from the perspective of a synaptic vesicle, we would see filaments and particles projecting from the presynaptic membrane, often forming a regular hexagonal arrangement called a presynaptic grid. Specific points along the grid are thought to be the vesicle release sites.

透明的突触囊泡（即不是致密的核心颗粒）被致密的细胞骨架蛋白网络锚定和移动。一些囊泡聚集在突触前膜与突触接触的部分附近;这些囊泡附着位点称为活动区。突触囊泡沿着活动区排列了几个深处，这些活动区是实际胞吐作用的区域。每个突触的活性区数量差异很大（图 13-3 中活性区在突触中用箭头标记）。中枢神经系统 （CNS） 中的大多数突触的活动区相对较少，通常只有 1 个，但偶尔多达 10 或 20 个（而神经肌肉接头有数百个）。如果我们能从突触小泡的角度观察活动区的突触前面，我们会看到从突触前膜伸出的细丝和颗粒，通常形成一个规则的六边形排列，称为突触前网格。沿网格的特定点被认为是囊泡释放部位。

Unlike the clear synaptic vesicles containing nonpeptide transmitters, dense-core secretory granules are distributed randomly throughout the cytoplasm of the synaptic terminus. They are not concentrated at the presynaptic density, and they do not appear to release their contents at the active zone. Although the molecular pathways that control exocytosis of the neuronal dense-core granules are still being elucidated, it appears that a rise in [Ca2+]i is a primary stimulus.

与含有非肽递质的透明突触囊泡不同，致密核心分泌颗粒随机分布在整个突触末端的细胞质中。它们不集中在突触前密度，并且它们似乎不会在活性区释放其内容物。尽管控制神经元致密核心颗粒胞吐作用的分子途径仍在阐明中，但 [Ca2+]i 的增加似乎是主要刺激因素。

[编辑] 1.3 突触后膜包含递质受体和许多聚集在突触后致密区的蛋白质

The postsynaptic membrane contains transmitter receptors and numerous proteins clustered in the postsynaptic density

The postsynaptic membrane lies parallel to the presynaptic membrane, and they are separated by a narrow synaptic cleft (~30 nm wide) that is filled with extracellular fluid. Transmitter molecules released from the presynaptic terminal must diffuse across the cleft to reach postsynaptic receptors. The most characteristic anatomical feature of the postsynaptic side is the postsynaptic density, a strip of granular material visible under the electron microscope on the cytoplasmic face of the membrane (see Fig. 13-3). The most important molecular feature of the postsynaptic side is the cluster of transmitter receptors embedded within the postsynaptic membrane. Staining methods that use specific antibodies, toxins, or ligands coupled to some visible tag molecule can reveal the positions of the receptors.

突触后膜与突触前膜平行，它们被一个充满细胞外液的狭窄突触裂隙（~30 nm 宽）隔开。从突触前末梢释放的递质分子必须穿过裂隙扩散才能到达突触后受体。突触后侧最具特征的解剖学特征是突触后致密，即在电子显微镜下在膜的细胞质表面可见的一条颗粒状物质（见图 13-3）。突触后侧最重要的分子特征是嵌入突触后膜内的递质受体簇。使用特异性抗体、毒素或配体与一些可见标签分子偶联的染色方法可以揭示受体的位置。

In >90% of all excitatory synapses in the CNS, the postsynaptic site is a dendritic spine. The ubiquity of spines implies that they serve prominent functions, but their small size (usually <1 μm long) makes their function extremely difficult to study. Spines come in a variety of shapes, and their density varies from one dendrite to another (Fig. 13-5); indeed, some central neurons have no spines. The postsynaptic density of spines (as for all central synapses) contains >30 proteins in high concentration, including transmitter receptors, protein kinases, a host of structural proteins, and proteins that are involved in endocytosis and glycolysis.

在 CNS 中 >90% 的兴奋性突触中，突触后部位是树突状棘。棘的普遍性意味着它们发挥着突出的功能，但它们的小尺寸（通常<1微米长）使得它们的功能极难研究。棘的形状多种多样，它们的密度因树突而异（图 13-5）;事实上，一些中枢神经元没有棘。棘的突触后密度（与所有中枢突触一样）包含 >30 种高浓度的蛋白质，包括递质受体、蛋白激酶、宿主结构蛋白，以及参与内吞作用和糖酵解的蛋白质。

Numerous functions for spines have been proposed. It may be that spines increase the opportunity for a dendrite to form synapses with nearby axons. Many hypotheses have focused on the possibility that spines isolate individual synapses from the rest of a cell. This isolation may be electrical or chemical; the narrow spine neck may reduce current flow or the diffusion of chemicals from the spine head into the dendritic shaft. Evidence suggests that the high electrical resistance of the spine neck can amplify the size of an excitatory postsynaptic potential within the spine while reducing its amplitude along the shaft of the dendrite; this mechanism may allow neurons to integrate larger numbers of synaptic inputs. Activation of some excitatory synapses allows substantial amounts of Ca2+ to enter the postsynaptic cell. Spines may compartmentalize this Ca2+, thus allowing it to rise to higher levels or preventing it from influencing other synapses on the cell. Because increases in postsynaptic [Ca2+]i are an essential trigger for many forms of long-term synaptic plasticity, an attractive but unproven possibility is that dendritic spines play an important role in the mechanisms of learning and memory.

已经提出了许多用于脊柱的功能。可能是棘增加了树突与附近轴突形成突触的机会。许多假说都集中在脊柱将单个突触与细胞其余部分隔离开来的可能性上。这种隔离可以是电气的或化学的;狭窄的棘颈可能会减少电流或化学物质从脊柱头扩散到树突轴。有证据表明，脊柱颈部的高电阻可以放大脊柱内兴奋性突触后电位的大小，同时减小其沿树突干的振幅;这种机制可能允许神经元整合更多的突触输入。一些兴奋性突触的激活允许大量 Ca2+ 进入突触后细胞。棘可以将这种 Ca2+ 区区，从而使其上升到更高的水平或防止它影响细胞上的其他突触。因为突触后 [Ca2+]i 的增加是许多形式的长期突触可塑性的重要触发因素，所以一个有吸引力但未经证实的可能性是树突棘在学习和记忆机制中起着重要作用。

[编辑] 1.4 弥散分布的神经元系统使用一些递质来调节大脑的一般兴奋性

Some transmitters are used by diffusely distributed systems of neurons to modulate the general excitability of the brain

The brain carries out many sensory, motor, and cognitive functions that require fast, specific, spatially organized neural connections and operations. Consider the detailed neural mapping that allows you to read this sentence or the precise timing required to play the piano. These functions require spatially focused networks (Fig. 13-6A).

大脑执行许多感觉、运动和认知功能，这些功能需要快速、特定、空间组织的神经连接和操作。考虑一下允许您阅读这句话的详细神经映射或弹奏钢琴所需的精确时间。这些功能需要空间聚焦的网络（图 13-6A）。

Other functions, such as falling asleep, waking up, becoming attentive, or changing mood, involve more general alterations of the brain. Several systems of neurons regulate the general excitability of the CNS. Each of these modulatory systems uses a different neurotransmitter, and the axons of each make widely dispersed, diffuse, almost meandering synaptic connections to carry a simple message to vast regions of the brain. This arrangement can be achieved by a widely divergent network (see Fig. 13-6B). The functions of the different systems are not well understood, but each appears to be essential for certain aspects of arousal, motor control, memory, mood, motivation, and metabolic state. The modulatory systems are of central importance to clinical medicine. Both the activity of psychoactive drugs and the pathological processes of most psychiatric disorders seem to involve alterations in one or more of the modulatory systems.

其他功能，例如入睡、醒来、变得专注或改变情绪，涉及大脑的更普遍改变。几个神经元系统调节 CNS 的一般兴奋性。这些调节系统中的每一个都使用不同的神经递质，每个系统的轴突建立广泛分散、弥散、几乎蜿蜒的突触连接，将简单的信息传递到大脑的广大区域。这种安排可以通过一个发散广泛的网络来实现（见图 13-6B）。不同系统的功能尚不清楚，但每个系统似乎对于唤醒、运动控制、记忆、情绪、动机和代谢状态的某些方面都是必不可少的。调节系统对临床医学至关重要。精神活性药物的活性和大多数精神疾病的病理过程似乎都涉及一个或多个调节系统的改变。

The brain has several modulatory systems with diffuse central connections. Although they differ in structure and function, they have certain similarities:

大脑有几个具有弥散性中央连接的调节系统。尽管它们在结构和功能上有所不同，但它们具有某些相似之处：

1. Typically, a small set of neurons (several thousand) forms the center of the system.

1. 通常，一小群神经元（数千个）构成系统的中心。

2. Neurons of the diffuse systems arise from the central core of the brain, most of them from the brainstem.

2. 弥散系统的神经元来自大脑的中央核心，其中大部分来自脑干。

3. Each neuron can influence many others because each one has an axon that may contact tens of thousands of postsynaptic neurons spread widely across the brain.

3. 每个神经元都可以影响许多其他神经元，因为每个神经元都有一个轴突，可以接触广泛分布在大脑中的数以万计的突触后神经元。

4. The synapses made by some of these systems seem designed to release transmitter molecules into the extracellular fluid so that they can diffuse to many neurons rather than be confined to the vicinity of a single synaptic cleft.

4. 其中一些系统产生的突触似乎旨在将递质分子释放到细胞外液中，以便它们可以扩散到许多神经元，而不是局限于单个突触间隙附近。

The main modulatory systems of the brain are distinct anatomically and biochemically. Separate systems use norepinephrine, serotonin (5-hydroxytryptamine [5-HT]), dopamine, ACh, or histamine as their neurotransmitter. They all tend to involve numerous metabotropic transmitter receptors (see p. 206). Unlike ionotropic receptors, which are themselves ion channels, metabotropic receptors are coupled to enzymes such as adenylyl cyclase or phospholipase C through G proteins. For example, the brain has 10 to 100 times more metabotropic (i.e., muscarinic) ACh receptors than ionotropic (i.e., nicotinic) ACh receptors. We briefly describe the anatomy and possible functions of each major system (Fig. 13-7).

大脑的主要调节系统在解剖学和生化学上是不同的。单独的系统使用去甲肾上腺素、血清素（5-羟色胺 [5-HT]）、多巴胺、ACh 或组胺作为其神经递质。它们都倾向于涉及许多代谢性递质受体（见第 206 页）。与本身是离子通道的离子型受体不同，代谢型受体通过 G 蛋白与腺苷酸环化酶或磷脂酶 C 等酶偶联。例如，大脑的代谢型（即毒蕈碱型）ACh 受体是离子型（即烟碱型）ACh 受体的 10 到 100 倍。我们简要描述了每个主要系统的解剖结构和可能的功能（图 13-7）。

Norepinephrine-containing neurons are in the tiny locus coeruleus (from the Latin for “blue spot” because of the pigment in its cells), located bilaterally in the brainstem (see Fig. 13-7A). Each human locus coeruleus has ~12,000 neurons. Axons from the locus coeruleus innervate just about every part of the brain: the entire cerebral cortex, the thalamus and hypothalamus, the olfactory bulb, the cerebellum, the midbrain, and the spinal cord. Just one of its neurons can make >250,000 synapses, and that cell can have one axon branch in the cerebral cortex and another in the cerebellar cortex! Locus coeruleus cells seem to be involved in the regulation of attention, arousal, and sleep-wake cycles as well as in learning and memory, anxiety and pain, mood, and brain metabolism. Recordings from awake rats and monkeys in behavioral studies show that locus coeruleus neurons are best activated by new, unexpected, nonpainful sensory stimuli in the animal’s environment. They are least active when the animals are not vigilant, just sitting around quietly digesting a meal. The locus coeruleus may participate in general arousal of the brain during interesting events in the outside world.

含去甲肾上腺素的神经元位于脑干双侧的微小蓝斑（来自拉丁语中的“蓝点”，因为它的细胞中有色素），（见图 13-7A）。每个人类蓝斑位点都有 ~12,000 个神经元。来自蓝斑的轴突几乎支配大脑的每个部分：整个大脑皮层、丘脑和下丘脑、嗅球、小脑、中脑和脊髓。只要它的一个神经元可以产生>250,000个突触，而这个细胞可以在大脑皮层中有一个轴突分支，在小脑皮层中可以有一个轴突分支！蓝斑细胞似乎参与注意力、唤醒和睡眠-觉醒周期的调节，以及学习和记忆、焦虑和疼痛、情绪和大脑新陈代谢。行为研究中清醒的大鼠和猴子的记录表明，蓝斑神经元最好被动物环境中新的、意想不到的、无痛的感觉刺激激活。当动物不警惕时，它们最不活跃，只是静静地坐在那里消化一顿饭。蓝斑可能在外界的有趣事件中参与大脑的一般唤醒。

Serotonin-containing neurons are mostly clustered within the nine raphé nuclei (see Fig. 13-7B). Raphé means “ridge” or “seam” in Greek, and indeed the raphé nuclei lie to either side of the midline of the brainstem. Each nucleus projects to different regions of the brain, and together they innervate most of the CNS in the same diffuse way as the locus coeruleus neurons. Similar to neurons of the locus coeruleus, cells of the raphé nuclei fire most rapidly during wakefulness, when an animal is aroused and active. Raphé neurons are quietest during certain stages of sleep. The locus coeruleus and the raphé nuclei are part of a venerable concept called the ascending reticular activating system, which implicates the reticular “core” of the brainstem in processes that arouse and awaken the forebrain. Raphé neurons seem to be intimately involved in the control of sleep-wake cycles as well as the different stages of sleep. Serotonergic raphé neurons have also been implicated in the control of mood and certain types of emotional behavior. Many hallucinogenic drugs, such as lysergic acid diethylamide (LSD), apparently exert their effects through interaction with serotonin receptors. Serotonin may also be involved in clinical depression; some of the most effective drugs now used to treat depression (e.g., fluoxetine [Prozac]) are potent blockers of serotonin re-uptake and thus prolong its action in the brain.

含血清素的神经元大多聚集在 9 个 raphé 核内（见图 13-7B）。Raphé 在希腊语中的意思是“脊”或“接缝”，事实上，raphé 核位于脑干中线的两侧。每个细胞核都投射到大脑的不同区域，它们一起以与蓝斑神经元相同的弥散方式支配大部分 CNS。与蓝斑的神经元类似，raphé 核的细胞在清醒时最迅速地放电，此时动物被唤醒并活跃。Raphé 神经元在睡眠的某些阶段是最安静的。蓝斑和 raphé 核是一个古老的概念的一部分，称为升位网状激活系统，它涉及脑干的网状“核心”参与唤醒和唤醒前脑的过程。Raphé 神经元似乎与睡眠-觉醒周期的控制以及睡眠的不同阶段密切相关。血清素能 raphé 神经元也与情绪和某些类型的情绪行为的控制有关。许多致幻药物，如麦角酸二乙胺 （LSD），显然通过与血清素受体的相互作用来发挥作用。血清素也可能与临床抑郁症有关;现在用于治疗抑郁症的一些最有效的药物（例如氟西汀 [百忧解]）是血清素再摄取的有效阻断剂，从而延长其在大脑中的作用。

Although dopamine-containing neurons are scattered throughout the CNS, two closely related groups of dopaminergic cells have characteristics of the diffuse modulatory systems (see Fig. 13-7C). One of these groups is the substantia nigra in the midbrain. Its cells project axons to the striatum, a part of the basal ganglia, and they somehow facilitate the initiation of voluntary movement. Degeneration of the dopamine-containing cells in the substantia nigra produces the progressively worsening motor dysfunction of Parkinson disease. Another set of dopaminergic neurons lies in the ventral tegmental area of the midbrain; these neurons innervate the part of the forebrain that includes the prefrontal cortex and parts of the limbic system. They have been implicated in neural systems that mediate reinforcement or reward as well as in aspects of drug addiction and psychiatric disorders, most notably schizophrenia. Members of the class of antipsychotic drugs called neuroleptics are antagonists of certain dopamine receptors.

尽管含多巴胺的神经元分散在整个 CNS 中，但两组密切相关的多巴胺能细胞具有弥漫性调节系统的特征（见图 13-7C）。其中一组是中脑中的黑质。它的细胞将轴突投射到纹状体（基底神经节的一部分），它们以某种方式促进了自主运动的启动。黑质中含多巴胺的细胞变性导致帕金森病的运动功能障碍进行性恶化。另一组多巴胺能神经元位于中脑的腹侧被盖区;这些神经元支配前脑的一部分，包括前额叶皮层和边缘系统的一部分。它们与介导强化或奖励的神经系统以及药物成瘾和精神疾病（最著名的是精神分裂症）方面有关。称为抗精神病药的一类抗精神病药物的成员是某些多巴胺受体的拮抗剂。

Acetylcholine is the familiar transmitter of the neuromuscular junction and the autonomic nervous system. Within the brain are two major diffuse modulatory cholinergic systems: the basal forebrain complex (which innervates the hippocampus and all of the neocortex) and the pontomesencephalotegmental cholinergic complex (which innervates the dorsal thalamus and parts of the forebrain) (see Fig. 13-7D). The functions of these systems are poorly understood, but interest has been fueled by evidence that they are involved in the regulation of general brain excitability during arousal and sleep-wake cycles as well as perhaps in learning and memory formation.

乙酰胆碱是神经肌肉接头和自主神经系统的常见递质。大脑内有两个主要的弥漫性调节胆碱能系统：基底前脑复合体（支配海马体和所有新皮层）和脑桥脑胆碱能复合体（支配背丘脑和前脑部分）（见图 13-7D）。这些系统的功能知之甚少，但有证据表明它们参与唤醒和睡眠-觉醒周期期间一般大脑兴奋性的调节，并且可能参与学习和记忆形成，这激发了人们的兴趣。

Collectively, the diffuse modulatory systems may be viewed as providing general regulation of brain function, much like the autonomic nervous system (see Chapter 14) regulates the organ systems of the body. Because their axons spread so widely within the CNS, the few modulatory neurons can have an inordinately strong influence on behavior.

总的来说，弥散调节系统可以被视为提供大脑功能的一般调节，就像自主神经系统（见第 14 章）调节身体的器官系统一样。因为它们的轴突在 CNS 内传播得如此广泛，所以少数调节神经元可以对行为产生非常强大的影响。

[编辑] 1.5 电突触在哺乳动物神经系统中发挥着特殊功能

Electrical synapses serve specialized functions in the mammalian nervous system

Many cells are coupled to one another through gap junctions. The large and relatively nonselective gap junction channels (see p. 165) allow ion currents to flow in both directions (in most types of gap junctions) or unidirectionally (in rare types). It follows from Ohm’s law that if two cells are coupled by gap junctions and they have different membrane voltages, current will flow from one cell into the other (see Fig. 6-18C). If the first cell generates an action potential, current will flow through the gap junction channels and depolarize the second cell; this type of current flow, for example, is the basis for conduction of excitation across cardiac muscle. Such an arrangement has all the earmarks of a synapse, and indeed, when gap junctions interconnect neurons, we describe them as electrical synapses.

许多细胞通过间隙连接相互耦合。大且相对非选择性的间隙结通道（见第 165 页）允许离子电流双向流动（在大多数类型的间隙结中）或单向流动（在罕见类型中）。根据欧姆定律，如果两个电池通过间隙结耦合并且它们具有不同的膜电压，则电流将从一个电池流向另一个电池（见图 6-18C）。如果第一个电池产生动作电位，电流将流过间隙结通道并使第二个电池去极化;例如，这种类型的电流是磁激通过心肌传导的基础。这样的排列具有突触的所有特征，事实上，当间隙连接互连神经元时，我们将它们描述为电突触。

Electrical synapses would seem to have many advantages over chemical synapses: they are extremely fast and limited only by the time constants of the systems involved, they use relatively little metabolic energy or molecular machinery, they are highly reliable, and they can be bidirectional. Indeed, electrical synapses have now been observed in nearly every part of the mammalian CNS. They interconnect inhibitory neurons of the cerebral cortex and thalamus, excitatory neurons of the brainstem and retina, and a variety of other neurons in the hypothalamus, basal ganglia, and spinal cord. At nearly all of these sites, the gap junction protein connexin-36 (Cx36)—which is expressed exclusively in CNS neurons and β cells of the pancreas—is an essential component of the electrical synapse (see Fig. 6-18C). Glial cells in the brain express several other types of connexins. However, in all of the aforementioned sites, electrical synapses tend to be outnumbered by chemical synapses. Gap junctions universally interconnect the photoreceptors of the retina, astrocytes and other types of glia (see p. 289) throughout the CNS, and most types of cells early in development.

与化学突触相比，电突触似乎具有许多优势：它们速度极快，并且仅受所涉及系统的时间常数的限制，它们使用相对较少的代谢能或分子机制，它们高度可靠，并且可以是双向的。事实上，现在几乎在哺乳动物 CNS 的每个部分都观察到电突触。它们将大脑皮层和丘脑的抑制性神经元、脑干和视网膜的兴奋性神经元以及下丘脑、基底神经节和脊髓中的各种其他神经元相互连接。在几乎所有这些位点，间隙连接蛋白连接蛋白 36 （Cx36） — 仅在胰腺的 CNS 神经元和 β 细胞中表达 — 是电突触的重要组成部分（见图 6-18C）。大脑中的神经胶质细胞表达几种其他类型的连接蛋白。然而，在上述所有位点中，电突触的数量往往超过化学突触。间隙连接普遍互连整个 CNS 中视网膜、星形胶质细胞和其他类型的神经胶质细胞（见第 289 页）的光感受器，以及发育早期的大多数类型的细胞。

Why are chemical synapses, as complex and relatively slow as they are, more prevalent than electrical synapses in the mature brain? Comparative studies suggest several reasons for the predominance of chemical synapses among mammalian neurons. The first is amplification. Electrical synapses do not amplify the signal passed from one cell to the next; they can only diminish it. Therefore, if a presynaptic cell is small relative to its coupled postsynaptic cell, the current that it can generate through an electrical synapse will also be small, and thus “synaptic strength” will be low. By contrast, a small bolus of neurotransmitter from a chemical synapse can trigger an amplifying cascade of molecular events that can cause a relatively large postsynaptic change.

为什么在成熟大脑中，化学突触虽然复杂且相对缓慢，但比电突触更普遍？比较研究表明，化学突触在哺乳动物神经元中占主导地位的几个原因。首先是放大。电突触不会放大从一个细胞传递到另一个细胞的信号;他们只能减少它。因此，如果突触前细胞相对于其耦合的突触后细胞较小，则它可以通过电突触产生的电流也将很小，因此“突触强度”将较低。相比之下，来自化学突触的一小团神经递质可以触发分子事件的放大级联反应，从而导致相对较大的突触后变化。

A second advantage of chemical synapses is their ability to either excite or inhibit postsynaptic neurons selectively. Electrical synapses are not inherently excitatory or inhibitory, although they can mediate either effect under the right circumstances. Chemical synapses can reliably inhibit by simply opening channels that are selective for ions with relatively negative equilibrium potentials; they can excite by opening channels selective for ions with equilibrium potentials positive to resting potential.

化学突触的第二个优点是它们能够选择性地激发或抑制突触后神经元。电突触本身并不是兴奋性的或抑制性的，尽管它们可以在适当的情况下介导这两种作用。化学突触可以通过简单地打开对具有相对负平衡电位的离子具有选择性的通道来可靠地抑制;它们可以通过打开对离子选择性的通道进行激发，这些离子的平衡电位为正静息电位。

A third advantage of chemical synapses is that they can transmit information over a broad time domain. By using different transmitters, receptors, second messengers, and effectors, chemical synapses can produce a wide array of postsynaptic effects with time courses ranging from a few milliseconds to minutes and even hours. The effects of electrical synapses are generally limited to the time course of the presynaptic event.

化学突触的第三个优点是它们可以在很宽的时域上传输信息。通过使用不同的递质、受体、第二信使和效应器，化学突触可以产生广泛的突触后效应，时间过程从几毫秒到几分钟甚至几小时不等。电突触的影响通常仅限于突触前事件的时间进程。

A fourth advantage of chemical synapses is that they are champions of plasticity; their strength can be a strong function of recent neural activity, and they can therefore play a role in learning and memory, which are essential to the success of vertebrate species. Electrical synapses also display forms of long-term plasticity, although this has not been well studied in the mammalian CNS.

化学突触的第四个优点是它们是可塑性的冠军;它们的力量可以是近期神经活动的强大功能，因此它们可以在学习和记忆中发挥作用，这对脊椎动物物种的成功至关重要。电突触也显示出长期可塑性的形式，尽管这尚未在哺乳动物 CNS 中得到充分研究。

It might also be noted that the few perceived advantages of electrical synapses may be more apparent than real. Bidirectionality is clearly not useful in many neural circuits, and the difference in speed of transmission may be too small to matter in most cases. Electrical synapses serve important but specialized functions in the nervous system. They seem to be most prevalent in neural circuits in which speed or a high degree of synchrony is at a premium: quick-escape systems, the fine coordination of rapid eye movements, or the synchronization of neurons generating rhythmic activity. Gap junctions are also effective in diffusely spreading current through large networks of cells, which appears to be their function in photoreceptors and glia.

还可以注意到，电突触的少数感知优势可能比实际更明显。双向性在许多神经回路中显然没有用，而且在大多数情况下，传输速度的差异可能太小而无关紧要。电突触在神经系统中起着重要但特殊的功能。它们似乎在速度或高度同步至关重要的神经回路中最为普遍：快速逃脱系统、快速眼球运动的精细协调或神经元产生节律活动的同步。间隙连接还可有效地通过大型细胞网络扩散电流，这似乎是它们在光感受器和神经胶质细胞中的功能。

[编辑] 2 大脑的神经递质系统

NEUROTRANSMITTER SYSTEMS OF THE BRAIN

The mammalian nervous system uses dozens of different neurotransmitters that act on >100 types of receptors; these receptors stimulate numerous second-messenger systems, which in turn regulate several dozen ion channels and enzymes. We call these pathways of synaptic signaling the transmitter systems. It is not enough to know the identity of a transmitter to predict its effect—one must also know the nature of the components that it interacts with, and these components may vary from one part of the brain to another and even between parts of a single neuron. The components of the transmitter systems are extremely complex. This subchapter introduces the intricate and vital web of neurotransmitters. The clinical importance of the subject is difficult to overstate. It is likely that most drugs that alter mental function do so by interacting with neurotransmitter systems in the brain. Disorders of neurotransmitter systems are also implicated in many devastating brain disorders, such as schizophrenia, depression, epilepsy, Parkinson disease, the damage of stroke, and drug addiction.

哺乳动物的神经系统使用数十种不同的神经递质，这些神经递质作用于 >100 种受体；这些受体刺激许多第二信使系统，进而调节几十个离子通道和酶。我们将这些突触信号通路称为递质系统。仅仅知道递质的身份来预测其效果是不够的——还必须知道它与它相互作用的成分的性质，这些成分可能因大脑的一个部分而异，甚至在单个神经元的各个部分之间也不同。发射机系统的组件极其复杂。本小章介绍了神经递质的复杂而重要的网络。该学科的临床重要性怎么强调都不为过。大多数改变精神功能的药物很可能通过与大脑中的神经递质系统相互作用来实现。神经递质系统疾病也与许多毁灭性的脑部疾病有关，例如精神分裂症、抑郁症、癫痫、帕金森病、中风的损害和药物成瘾。

[编辑] 2.1 大脑的大多数递质是常见的生化物质

Most of the brain’s transmitters are common biochemicals

Most neurotransmitters are similar or identical to the standard chemicals of life, the same substances that all cells use for metabolism. Transmitter molecules can be large or small. The small ones, such as the amino acids glutamate, aspartate, GABA, and glycine, are also simple foods (Fig. 13-8A). Cells use amino acids as an energy source and for construction of essential proteins, but they have co-opted these common molecules for essential and widespread messenger functions in the brain. Another important class of small neurotransmitters is the amines, including the monoamines (e.g., ACh, serotonin, and histamine) listed in Figure 13-8B and the catecholamines (e.g., dopamine, norepinephrine, and epinephrine) listed in Figure 13-8C. Neurons synthesize these small transmitters by adding only a few chemical steps to the glucose and amino-acid pathways that are present in every cell. Purine derivatives can also be important transmitters. For example, a key molecule of cell metabolism that also serves as a neurotransmitter is ATP, which is the major chemical intermediate of energy metabolism and is present in many synaptic vesicles. It is also released from various synapses in the central and peripheral nervous systems. ATP appears to be the transmitter responsible for sympathetic vasoconstriction in small arteries and arterioles, for example. ATP acts on a variety of nucleotide receptors, both ionotropic and metabotropic. Adenosine is also a transmitter in the CNS.

大多数神经递质与生命的标准化学物质相似或相同，所有细胞都用于新陈代谢的相同物质。递质分子可大可小。小的食物，如氨基酸谷氨酸、天冬氨酸、GABA 和甘氨酸，也是简单的食物（图 13-8A）。细胞使用氨基酸作为能量来源和构建必需蛋白质，但它们将这些常见分子用于大脑中基本和广泛的信使功能。另一类重要的小神经递质是胺类，包括图 13-8B 中列出的单胺（例如，ACh、血清素和组胺）和图 13-8C 中列出的儿茶酚胺（例如，多巴胺、去甲肾上腺素和肾上腺素）。神经元通过向每个细胞中存在的葡萄糖和氨基酸途径添加几个化学步骤来合成这些小递质。嘌呤衍生物也可以是重要的递质。例如，细胞代谢的一个关键分子也用作神经递质，它是能量代谢的主要化学中间体，存在于许多突触囊泡中。它也从中枢和周围神经系统的各种突触中释放。例如，ATP 似乎是负责小动脉和小动脉交感血管收缩的递质。ATP 作用于多种核苷酸受体，包括离子型和代谢型。腺苷也是 CNS 中的递质。

The large-molecule transmitters, which constitute a much more numerous group, are proteins or small bits of protein called neuroactive peptides. A few of the better-studied neuropeptides are shown in Figure 13-9. Many were originally identified in non-neural tissues such as the gut or endocrine glands and were only later found in nerve terminals of the brain or peripheral nervous system. They vary in size from dipeptides (e.g., N-acetylaspartylglutamate) to large polypeptides. Among the neuroactive peptides are the endorphins (endogenous substances with morphine-like actions), which include small peptides called enkephalins. The term opioids refers to all substances with a morphinelike pharmacology—the endorphins (endogenous) as well as morphine and heroin (exogenous).

构成数量更多的大分子递质是蛋白质或称为神经活性肽的小蛋白质片段。一些研究较好的神经肽如图 13-9 所示。许多最初是在非神经组织（如肠道或内分泌腺）中发现的，后来才在大脑或周围神经系统的神经末梢中发现。它们的大小从二肽（例如 N-乙酰乙酰谷氨酸）到大多肽不等。神经活性肽包括内啡肽（具有吗啡样作用的内源性物质），其中包括称为脑啡肽的小肽。阿片类药物一词是指所有具有吗啡样药理学的物质——内啡肽（内源性）以及吗啡和海洛因（外源性）。

The synthesis of most neuropeptides begins like that of any other secretory protein (see p. 34), with the ribosomedirected assembly of a large prehormone. The prehormone is then cleaved to form a smaller prohormone in the Golgi apparatus and further reduced into small active neuropeptides that are packaged into vesicles. Thus, the synthesis of neuropeptides differs significantly from that of the small transmitters.

大多数神经肽的合成与任何其他分泌蛋白一样开始（见第 34 页），由核糖体定向组装一个大的激素前体。然后，前激素被裂解，在高尔基体中形成更小的激素原，并进一步还原成包装成囊泡的小活性神经肽。因此，神经肽的合成与小递质的合成显着不同。

In summary, then, the neurotransmitters consist of a dozen or so small molecules plus 50 to 100 peptides of various sizes. The small transmitters are, as a rule, each stored and released by separate sets of neurons, although some types of neurons do use two or more small transmitters. The peptides, however, are usually stored and released from the same neurons that use one of the small transmitters (Table 13-1), an arrangement called colocalization of neurotransmitters. Thus, GABA may be paired with somatostatin in some synapses, serotonin and enkephalin in others, and so on. The colocalized transmitters may be released together, but of course each acts on its own receptors. In addition, both clear and dense-core vesicles contain ATP as well as their primary transmitter.

总而言之，神经递质由十几个小分子和 50 到 100 个大小不一的肽组成。通常，每个小递质都由不同的神经元组存储和释放，尽管某些类型的神经元确实使用两个或多个小递质。然而，肽通常是从使用一种小递质的相同神经元储存和释放的（表 13-1），这种排列称为神经递质共定位。因此，GABA 可能在某些突触中与生长抑素配对，在其他突触中与血清素和脑啡肽配对，依此类推。共定位的递质可以一起释放，但当然每个递质都作用于自己的受体。此外，透明和致密核心囊泡都含有 ATP 及其主要递质。

One of the unique substances functioning as a transmitter is a gaseous molecule, the labile free radical nitric oxide (NO). Carbon monoxide (CO) and hydrogen sulfide (H2S) may also serve as transmitters, although evidence thus far is equivocal. NO is synthesized from L-arginine by many cells of the body (see p. 66). NO and CO can exert powerful biological effects by activating guanylyl cyclase, which converts GTP to cGMP. As a neurotransmitter, NO may have unique functions. It seems to be released from both presynaptic and what we normally think of as postsynaptic neurons. Because NO is not packaged into vesicles, its release does not require an increase in [Ca2+]i, although its synthesis does. NO may sometimes act as a retrograde messenger, that is, from postsynaptic to presynaptic structures. N13-2 Because NO is small and membrane permeable, it can diffuse about much more freely than other transmitter molecules, even penetrating through one cell to affect another beyond it. On the other hand, NO is evanescent, and it breaks down rapidly. The functions of gaseous transmitters (or “gasotransmitters”) are now being vigorously studied and hotly debated.

作为递质的独特物质之一是气态分子，不稳定的自由基一氧化氮 （NO）。一氧化碳 （CO） 和硫化氢 （H2S） 也可能作为递质，尽管迄今为止的证据尚模棱两可。NO 是由身体的许多细胞从 L-精氨酸合成的（见第 66 页）。NO 和 CO 可以通过激活鸟苷酸环化酶发挥强大的生物效应，鸟苷酸环化酶将 GTP 转化为 cGMP。作为一种神经递质，NO 可能具有独特的功能。它似乎从突触前神经元和我们通常认为的突触后神经元中释放出来。因为 NO 没有被包装到囊泡中，所以它的释放不需要 [Ca2+]i 的增加，尽管它的合成需要。NO 有时可能充当逆行信使，即从突触后结构到突触前结构。N13-2 因为 NO 很小且具有膜渗透性，所以它可以比其他递质分子更自由地扩散，甚至可以穿透一个细胞影响它之外的另一个细胞。另一方面，NO 是转瞬即逝的，它会迅速分解。气体发射器（或“气体发射器”）的功能现在正在被大力研究和激烈辩论。

The endocannabinoids are another unusual group of putative neurotransmitters. They include the endogenous lipophilic molecules anandamide (from ananda, the Sanskrit word for “internal bliss”) and 2-arachidonoyl glycerol (2-AG), both of which are arachidonic acid metabolites. These substances are called endocannabinoids because they mimic Δ9-tetrahydrocannabinol (THC), the active ingredient in marijuana, by binding to and activating specific G protein–coupled “cannabinoid” receptors. Remarkably, the brain has more cannabinoid receptors than any other GPCR type. Certain activated neurons synthesize and release endocannabinoids, which move readily across membranes to presynaptic terminals and modulate the further release of conventional transmitters such as GABA and glutamate. Their normal role in the brain is currently unknown. However, activation of cannabinoid receptors with low doses of THC leads to euphoria, relaxed sensations, decreased pain, and increased hunger; it can also impair problem-solving ability, short-term memory, and motor skills. High doses can alter personality and sometimes trigger hallucinations. THC and related drugs have promise for treatment of the nausea and vomiting of cancer patients undergoing chemotherapy, suppression of chronic pain, and stimulation of appetite in some patients with acquired immunodeficiency syndrome (AIDS).

内源性大麻素是另一组不寻常的推定神经递质。它们包括内源性亲脂性分子安非他命（来自 ananda，梵语中意为“内在的幸福”）和 2-花生四烯酰甘油 （2-AG），两者都是花生四烯酸代谢物。这些物质被称为内源性大麻素，因为它们通过与特定的 G 蛋白偶联的 “大麻素 ”受体结合并激活大麻中的活性成分 Δ9-四氢大麻酚 （THC） 来模仿。值得注意的是，大脑的大麻素受体比任何其他 GPCR 类型都多。某些激活的神经元合成并释放内源性大麻素，这些内源性大麻素很容易穿过膜到达突触前末端，并调节常规递质（如 GABA 和谷氨酸）的进一步释放。它们在大脑中的正常作用目前尚不清楚。然而，用低剂量的 THC 激活大麻素受体会导致欣快感、放松感、减轻疼痛和增加饥饿感;它还会损害解决问题的能力、短期记忆和运动技能。高剂量可以改变性格，有时会引发幻觉。THC 和相关药物有望治疗接受化疗的癌症患者的恶心和呕吐、抑制慢性疼痛和刺激一些获得性免疫缺陷综合症 （AIDS） 患者的食欲。

Most of the chemicals we call neurotransmitters also exist in non-neural parts of the body. Each chemical may serve dual purposes in that it can mediate communication in the nervous system but do something similar or even entirely different elsewhere. Amino acids, of course, are used to make protein everywhere. NO is a local hormone that relaxes the smooth muscle in blood vessels (see p. 480). Surprisingly, the cells with the highest ACh levels are in the cornea of the eye, although corneal cells lack specific receptors for ACh. It is not clear what ACh does for corneal cells, but it almost certainly is not acting as a transmitter. One of the most interesting nonmessenger functions of transmitter molecules is their role in the development of the brain, even before synapses have appeared. At these early stages of development, transmitters may regulate cell proliferation, migration, and differentiation, somehow helping to form the brain before they help operate it.

我们称为神经递质的大多数化学物质也存在于身体的非神经部位。每种化学物质可能具有双重目的，因为它可以介导神经系统中的交流，但在其他地方做类似甚至完全不同的事情。当然，氨基酸无处不在地被用来制造蛋白质。NO 是一种局部激素，可松弛血管中的平滑肌（见第 480 页）。令人惊讶的是，ACh 水平最高的细胞位于眼睛的角膜中，尽管角膜细胞缺乏 ACh 的特异性受体。目前尚不清楚 ACh 对角膜细胞有什么作用，但几乎可以肯定它不充当递质。递质分子最有趣的非信使功能之一是它们在大脑发育中的作用，甚至在突触出现之前。在发育的早期阶段，递质可能会调节细胞增殖、迁移和分化，以某种方式帮助在它们帮助操作大脑之前形成大脑。

[编辑] 2.2 突触递质可以刺激、抑制或调节突触后神经元

Synaptic transmitters can stimulate, inhibit, or modulate the postsynaptic neuron

Each neuromuscular junction has a simple and stereotyped job: when an action potential fires in the motor neuron, the junction must reliably excite its muscle cell to fire an action potential and contract. Decisions about muscle contractions (where, when, and how much) are made within the CNS, and the neuromuscular junction exists simply to communicate that decision to the muscle unambiguously and reliably. To perform this function, neuromuscular transmission has evolved to be very strong so that it is fail-safe under even the most extreme of physiological conditions.

每个神经肌肉接头都有一个简单而刻板的工作：当动作电位在运动神经元中触发时，该接头必须可靠地激发其肌肉细胞以触发动作电位并收缩。关于肌肉收缩（位置、时间和多少）的决定是在 CNS 内做出的，神经肌肉接头的存在只是为了明确可靠地将该决定传达给肌肉。为了执行此功能，神经肌肉传递已经进化到非常强大，因此即使在最极端的生理条件下也是故障安全的。

Synapses between neurons usually have a more subtle role in communication, and they use a variety of mechanisms to accomplish their more complex tasks. Like neuromuscular junctions, some neuron-neuron synapses (excitatory) can rapidly excite. However, other synapses (inhibitory) can cause profound inhibition by decreasing postsynaptic excitability directly (postsynaptic inhibition). In a third broad class of synapse (modulatory), the synapse often has little or no direct effect of its own but instead regulates or modifies the effect of other excitatory or inhibitory synapses by acting on either presynaptic or postsynaptic membranes. These three basic types of neural synapses are exemplified by their input to the pyramidal neuron of the cerebral cortex. In the example shown in Figure 13-10, a pyramidal neuron in the visual cortex receives an excitatory synaptic input from the thalamus (with glutamate as the neurotransmitter), an inhibitory synaptic input from an interneuron (with GABA as the neurotransmitter), and a modulatory input from the locus coeruleus (with norepinephrine as the neurotransmitter).

神经元之间的突触通常在交流中起着更微妙的作用，它们使用各种机制来完成更复杂的任务。与神经肌肉接头一样，一些神经元-神经元突触（兴奋性）可以快速兴奋。然而，其他突触（抑制性）可以通过直接降低突触后兴奋性（突触后抑制）来引起深度抑制。在第三大类突触（调节性）中，突触本身通常几乎没有或没有直接影响，而是通过作用于突触前或突触后膜来调节或改变其他兴奋性或抑制性突触的作用。这三种基本类型的神经突触可以通过它们对大脑皮层锥体神经元的输入来举例说明。在图 13-10 所示的示例中，视觉皮层中的锥体神经元接收来自丘脑的兴奋性突触输入（以谷氨酸为神经递质），从中间神经元接收抑制性突触输入（以 GABA 为神经递质）和来自蓝斑的调节输入（以去甲肾上腺素作为神经递质）。

Excitatory Synapses Pyramidal cells receive excitatory inputs from many sources, including the axons of the thalamus. Most fast excitatory synapses in the brain use glutamate as their transmitter, and the thalamus–to–cerebral cortex synapses are no exception (see Fig. 13-10). Aspartate may also be a transmitter in some regions of the CNS. Both amino acids have similar effects on the postsynaptic excitatory amino-acid receptors. For convenience, these types of synapses are often presumptuously referred to as glutamatergic. These excitatory amino acids bind to a group of fast ligandgated cation channels. When activated by synaptic glutamate, glutamate-gated channels generate an excitatory postsynaptic potential (EPSP) that is very similar to the one produced by ACh at the neuromuscular junction (see p. 210), except that it is usually much smaller than the EPSP in muscle. In the example shown in Figure 13-11 (left side), glutamate produces the EPSP by activating a nonselective cation channel that has about the same conductance for Na+ and K+. Thus, the reversal potential (see p. 146) of the EPSP is ~0 mV, about midway between the equilibrium potential for Na+ (ENa) and that for K+ (EK). An EPSP from the activation of a single glutamatergic synapse in the cerebral cortex peaks at 0.01 to a few millivolts (depending on many factors, including the size of the postsynaptic cell and the size of the synapse), whereas one neuromuscular EPSP reaches a peak of ~40 mV—a difference of 40- to 4000-fold. Obviously, most glutamatergic synapses are not designed to be fail-safe. It takes the summation of EPSPs from many such synapses to depolarize a postsynaptic neuron to the threshold for triggering an action potential.

兴奋性突触 锥体细胞接收来自许多来源的兴奋性输入，包括丘脑的轴突。大脑中的大多数快速兴奋性突触都使用谷氨酸作为其递质，丘脑到大脑皮层的突触也不例外（见图 13-10）。天冬氨酸也可能是 CNS 某些区域的递质。两种氨基酸对突触后兴奋性氨基酸受体具有相似的作用。为方便起见，这些类型的突触通常被自以为是地称为谷氨酸能突触。这些兴奋性氨基酸与一组快速配体门控阳离子通道结合。当被突触谷氨酸激活时，谷氨酸门控通道产生兴奋性突触后电位 （EPSP），该电位与 ACh 在神经肌肉接头处产生的电位非常相似（见第 210 页），不同之处在于它通常比肌肉中的 EPSP 小得多。在图 13-11（左侧）所示的示例中，谷氨酸通过激活对 Na+ 和 K+ 具有大致相同电导的非选择性阳离子通道来产生 EPSP。因此，EPSP 的反转电位（见第 146 页）为 ~0 mV，大约介于 Na+ （ENa） 和 K+ （EK） 的平衡电位之间。大脑皮层中单个谷氨酸能突触激活的 EPSP 峰值为 0.01 至几毫伏（取决于许多因素，包括突触后细胞的大小和突触的大小），而一个神经肌肉 EPSP 达到 ~40 mV 的峰值——相差 40 至 4000 倍。显然，大多数谷氨酸能突触并不是为了故障安全而设计的。它需要将来自许多此类突触的 EPSP 相加，才能将突触后神经元去极化到触发动作电位的阈值。

Inhibitory Synapses Skeletal muscle cells in vertebrates have only excitatory synapses. On the other hand, virtually all central neurons have numerous excitatory and inhibitory synapses. Thus, the excitability of most neurons at any moment is governed by the dynamic balance of excitation and inhibition. The inhibitory transmitters GABA and glycine are the transmitters at the large majority of inhibitory synapses. Indeed, the inhibitory synapse between the interneuron and the pyramidal cell in Figure 13-10 uses GABA. Both GABA and glycine bind to receptors that gate Cl−-selective channels (see p. 213). Cl− conductance usually has an inhibitory influence because the equilibrium potential for Cl− (ECl) in neurons is near or slightly negative to the resting potential of the neuron. Thus, the reversal potential for the Cl−-mediated inhibitory postsynaptic potential (IPSP) is the same as the ECl. If Cl− conductance increases, the Vm has a tendency to move toward ECl (see Fig. 13-11, right side). The effect is inhibitory because it tends to oppose other factors (mainly EPSPs) that might otherwise move the Vm toward or above the threshold for an action potential.

抑制性突触 脊椎动物中的骨骼肌细胞只有兴奋性突触。另一方面，几乎所有的中枢神经元都有许多兴奋性和抑制性突触。因此，大多数神经元在任何时刻的兴奋性都受兴奋和抑制的动态平衡的控制。抑制性递质 GABA 和甘氨酸是绝大多数抑制性突触的递质。事实上，图 13-10 中中间神经元和锥体细胞之间的抑制突触使用了 GABA。GABA 和甘氨酸都与设门 Cl 选择性通道的受体结合（见第 213 页）。Cl− 电导通常具有抑制作用，因为神经元中 Cl− （ECl） 的平衡电位接近或略微负神经元的静息电位。因此，Cl - 介导的抑制性突触后电位 （IPSP） 的逆转电位与 ECl 相同。如果 Cl− 电导增加，Vm 有向 ECl 移动的趋势（参见图 13-11，右侧）。这种效果是抑制性的，因为它倾向于对抗其他因素（主要是 EPSP），否则这些因素可能会使 Vm 接近或高于动作电位的阈值。

[编辑] 2.3 G 蛋白可以通过第二信使直接或间接影响离子通道

G proteins may affect ion channels directly, or indirectly through second messengers

GPCRs exist in every cell (see pp. 51–66). In the preceding section we described one example, the receptor for norepinephrine and its second messenger–mediated effect on certain K+ channels. However, norepinephrine alone has at least five major receptor types—two α receptors and three β receptors—that act on numerous effectors. In fact, each transmitter has multiple GPCRs, and their effects are complex and interactive and engage almost all aspects of cell function through several intracellular messenger systems. The various GPCRs can recognize a wide range of transmitter types, from small molecules to peptides.

GPCR 存在于每个细胞中（参见第 51-66 页）。在上一节中，我们描述了一个例子，去甲肾上腺素受体及其对某些 K+ 通道的第二信使介导的作用。然而，单独的去甲肾上腺素至少有五种主要受体类型——两种α受体和三种β受体——作用于许多效应器。事实上，每个递质都有多个 GPCR，它们的作用是复杂且相互作用的，并通过多个细胞内信使系统参与细胞功能的几乎所有方面。各种 GPCR 可以识别从小分子到肽的各种递质类型。

Activated G proteins can trigger a wide array of responses at synapses by either of the two general pathways introduced in Chapter 3: (1) the G protein may modulate the gating of an ion channel directly or by a very short second-messenger pathway, and (2) the G protein may activate one of several enzyme systems that involve second messengers and subsequent signal cascades.

活化的 G 蛋白可以通过第 3 章中介绍的两种一般途径中的任何一种在突触处触发多种反应：（1） G 蛋白可以直接或通过非常短的第二信使途径调节离子通道的门控，以及 （2） G 蛋白可以激活涉及第二信使和后续信号级联的几种酶系统之一。

The first—and simplest—G-protein cascade involves a direct linkage from the receptor to the G protein to the channel and is sometimes called the membrane-delimited pathway. N13-3 In this case the G protein may be the only messenger between the receptor and the effector. A variety of neurotransmitters use this pathway. For example, in heart muscle, ACh binds to a certain type of muscarinic ACh receptor (M2) that activates a G protein, the βγ subunits of which in turn cause a K+ channel to open (see Fig. 13-13B, below). Other receptors in various cells can modulate other K+ and Ca2+ channels in a similar way.

第一个也是最简单的 G 蛋白级联反应涉及从受体到 G 蛋白再到通道的直接连接，有时称为膜分隔通路。N13-3 在这种情况下，G 蛋白可能是受体和效应子之间唯一的信使。多种神经递质都使用这条通路。例如，在心肌中，ACh 与某种类型的毒蕈碱 ACh 受体 （M2） 结合，该受体激活 G 蛋白，其 βγ 亚基反过来导致 K+ 通道打开（见下图 13-13B）。各种细胞中的其他受体可以以类似的方式调节其他 K+ 和 Ca2+ 通道。

One advantage of the membrane-delimited pathway is that it is relatively fast, beginning within 30 to 100 ms—not quite as fast as a ligand-gated channel, which uses no intermediary between receptor and channel, but faster than the many-messenger cascades described next. The membranedelimited pathway is also localized in comparison to the other cascades. Because the G protein cannot diffuse very far within the membrane, only channels nearby can be affected. This type of coupling also allows flexibility because many types of receptors can be coupled to a variety of channels by use of the appropriate G-protein intermediate.

膜分隔通路的一个优点是它相对较快，从 30 到 100 毫秒开始，不如配体门控通道快，配体门控通道在受体和通道之间不使用中介，但比下面描述的多信使级联反应更快。与其他级联反应相比，膜分隔通路也位于该通路。因为 G 蛋白不能在膜内扩散得很远，所以只有附近的通道会受到影响。这种类型的偶联还允许灵活性，因为通过使用适当的 G 蛋白中间体，可以将许多类型的受体偶联到各种通道。

The other general type of G-protein signaling involves enzyme systems and second messengers, often diffusing through the cytoplasm, to influence an ion channel. The terminology deserves some clarification. Traditionally, the small, diffusible intracellular chemicals (e.g., cAMP, inositol 1,4,5-trisphosphate [IP3]) that help carry the message between a transmitter receptor and a channel are called second messengers. The transmitter itself is counted as the first messenger, but notice that by this logic the receptor is not a messenger at all, even though it transfers a signal from the neurotransmitter to a G protein. The G protein is also not counted as a messenger, nor are the various enzymes that may come before and after the traditional second messenger in any signal cascade. Different cascades involve different numbers of messengers, but obviously, most have many more than two! Alas, the terminology is entrenched, although when we speak of second messengers, one should remember that a multiple-messenger cascade is almost always involved. As an added complication, two or more cascades, each with different types of messengers, may sometimes be activated by one type of receptor (an example of divergence; see below).

另一种一般类型的 G 蛋白信号传导涉及酶系统和第二信使，通常通过细胞质扩散，以影响离子通道。术语值得澄清。传统上，有助于在递质受体和通道之间传递信息的小而可扩散的细胞内化学物质（例如 cAMP、肌醇 1,4,5-三磷酸 [IP3]）称为第二信使。递质本身算作第一个信使，但请注意，按照这种逻辑，受体根本不是信使，即使它将信号从神经递质转移到 G 蛋白。G 蛋白也不算作信使，在任何信号级联中传统第二信使之前和之后可能出现的各种酶也不算作信使。不同的级联涉及不同数量的信使，但显然，大多数都有不止两个！唉，这个术语是根深蒂固的，尽管当我们谈到第二信使时，我们应该记住，几乎总是涉及多信使级联。作为额外的并发症，两个或多个级联反应，每个级联反应都有不同类型的信使，有时可能被一种类型的受体激活（发散的一个例子，见下文）。

In Chapter 3, we discussed three of these longer, and slower, G-protein signal cascades: (1) the adenylyl cyclase pathway, (2) the phospholipase C pathway, and (3) the phospholipase A2 pathway. Each is activated by a different set of receptors, each uses a different G protein, and each generates different intracellular messengers. Some of these messengers dissolve in the watery cytoplasm, whereas others diffuse within the fatty lipid bilayer. The final link in most of the messenger cascades is a kinase.

在第 3 章中，我们讨论了其中三个较长且较慢的 G 蛋白信号级联反应：（1） 腺苷酸环化酶途径，（2） 磷脂酶 C 途径，以及 （3） 磷脂酶 A2 途径。每个受体都由一组不同的受体激活，每个受体使用不同的 G 蛋白，并且每个受体都产生不同的细胞内信使。其中一些信使溶解在水状细胞质中，而另一些则在脂肪脂质双层内扩散。大多数信使级联反应的最后一个环节是激酶。

In a well-known example, cAMP binds to cAMPdependent protein kinase (protein kinase A), which then phosphorylates amino acids on K+ or Ca2+ channels in the membrane. The addition of phosphate groups to the channel protein changes its conformation slightly, which may strongly influence its probability of being open (see p. 163). On page 542 we discuss the stimulation of the β adrenergic receptor by norepinephrine, which ultimately results in a stronger heartbeat through phosphorylation and opening of myocardial voltage-gated Ca2+ channels. In the pyramidal cell of the hippocampus, stimulation of β adrenergic receptors increases [cAMP]i, which can activate Ca2+ channels but also inhibit some K+ channels. As a result, the cell can fire more action potentials during prolonged stimuli (see Fig. 13-12).

在一个众所周知的例子中，cAMP 与 cAMP 依赖性蛋白激酶（蛋白激酶 A）结合，然后磷酸化膜中 K+ 或 Ca2+ 通道上的氨基酸。向通道蛋白中添加磷酸基团会略微改变其构象，这可能会强烈影响其开放的可能性（参见第 163 页）。在第 542 页，我们讨论了去甲肾上腺素刺激 β 肾上腺素能受体，最终通过磷酸化和心肌电压门控 Ca2+ 通道的开放导致更强的心跳。在海马体的锥体细胞中，刺激 β 肾上腺素能受体会增加 [cAMP]i，这可以激活 Ca2+ 通道，但也抑制一些 K+ 通道。因此，细胞可以在长时间的刺激中激发更多的动作电位（见图 13-12）。

If transmitter-stimulated kinases were allowed to madly phosphorylate without some method of reversing the process, all proteins would quickly become saturated with phosphates and further regulation would become impossible. Protein phosphatases save the day. They act rapidly to remove phosphate groups (see pp. 57–58), and thus the degree of channel phosphorylation at any moment depends on the dynamic balance of phosphorylation and dephosphorylation.

如果允许递质刺激的激酶疯狂磷酸化，而没有某种逆转该过程的方法，则所有蛋白质将很快被磷酸盐饱和，并且无法进一步调节。蛋白质磷酸酶可以挽救局面。它们迅速作用以去除磷酸基团（参见第 57-58 页），因此任何时候通道磷酸化的程度取决于磷酸化和去磷酸化的动态平衡。

[编辑] 2.4 信号级联允许放大、调节和较长的递质响应持续时间

Signaling cascades allow amplification, regulation, and a long duration of transmitter responses

At this point you may be wondering about the perversity of such complex, interconnected, indirect messenger cascades. Do these long chains of command have any benefit? Why not use simple, fast, ligand-gated channels (Fig. 13-13A) for all transmitter purposes? In fact, complex messenger cascades seem to have advantages.

在这一点上，你可能想知道这种复杂、相互关联、间接的信使级联的反常性。这些长长的指挥链有什么好处吗？为什么不对所有发射机使用简单、快速的配体门控通道（图 13-13A）呢？事实上，复杂的信使级联似乎有优势。

One important advantage is amplification. When activated, one ligand-gated channel is just that: one ion channe in one place. However, when activated, one GPCR potentially influences many channels. Signal amplification can occur at several places in the cascade (see p. 51), and a few transmitter molecules can generate a sizable cellular effect. One stimulated receptor can activate perhaps 10 to 20 G proteins, each of which can activate a channel by a membranedelimited pathway such as the βγ pathway (see Fig. 13-13B). Alternatively, the α subunit of one G protein can activate an adenylyl cyclase, which can make many cAMP molecules, and the cAMP molecules can spread to activate many kinases; each kinase can then phosphorylate many channels (see Fig. 13-13C). If all cascade components were tied together in a clump, signaling would be severely limited. The use of small messengers that can diffuse quickly also allows signaling at a distance, over a wide stretch of cell membrane. N3-4 Signaling cascades also provide many sites for further regulation as well as interaction between cascades. Finally, signal cascades can generate long-lasting chemical changes in cells, which may form the basis for, among other things, a lifetime of memories.

一个重要的优点是扩增。激活后，一个配体门控通道就是：一个离子通道在一个地方。但是，当激活时，一个 GPCR 可能会影响多个通道。信号放大可以发生在级联反应的几个地方（参见第 51 页），并且一些递质分子可以产生相当大的细胞效应。一个受刺激的受体可以激活大约 10 到 20 G 的蛋白质，每个蛋白质都可以通过膜分隔的通路（如 βγ 通路）激活一个通道（见图 13-13B）。或者，一种 G 蛋白的 α 亚基可以激活腺苷酸环化酶，腺苷酸环化酶可以产生许多 cAMP 分子，并且 cAMP 分子可以扩散以激活许多激酶;然后，每种激酶都可以磷酸化许多通道（参见图 13-13C）。如果所有级联组件都捆绑在一起，则信号传输将受到严重限制。使用可快速弥散的小信使也允许在较宽的细胞膜上远距离进行信号转导。N3-4 信号转导级联还为进一步调节以及级联之间的相互作用提供了许多位点。最后，信号级联可以在细胞中产生持久的化学变化，这可能构成一生记忆的基础。

[编辑] 2.5 神经递质可能具有收敛和发散效应

Neurotransmitters may have both convergent and divergent effects

Two of the most common neurotransmitters in the brain are glutamate and GABA. Either molecule can bind to any of several kinds of receptors, and each of these receptors can mediate a different effect. This ability of one transmitter to activate more than one type of receptor is sometimes called divergence.

大脑中最常见的两种神经递质是谷氨酸和 GABA。任何一种分子都可以与几种受体中的任何一种结合，并且这些受体中的每一种都可以介导不同的作用。一种递质激活多种受体的这种能力有时称为发散。

Divergence is a rule among neurotransmitters. Nearly every well-studied transmitter can activate multiple receptor subtypes. Divergence means that one transmitter can affect different neurons (or even different parts of the same neuron) in very different ways. It also means that if a transmitter affects different neurons in different ways, it could be because each neuron has a different type of receptor. However, among transmitter systems that use second messengers, divergence may also occur at points beyond the level of the receptor. For example, norepinephrine can turn on or turn off a variety of ion channels in different cells (Fig. 13-14A). Some of these effects occur because norepinephrine activates different receptors, but some of these receptors may each activate more than one second messenger, or a single second messenger (e.g., cAMP) may activate a kinase that influences numerous different channels. Divergence may occur at any stage in the cascade of transmitter effects.

发散是神经递质之间的一条规则。几乎所有经过充分研究的递质都可以激活多种受体亚型。发散意味着一个递质可以以非常不同的方式影响不同的神经元（甚至同一神经元的不同部分）。这也意味着，如果递质以不同的方式影响不同的神经元，这可能是因为每个神经元都有不同类型的受体。然而，在使用第二信使的递质系统中，发散也可能发生在受体水平以外的点。例如，去甲肾上腺素可以打开或关闭不同细胞中的各种离子通道（图 13-14A）。其中一些作用的发生是因为去甲肾上腺素激活不同的受体，但其中一些受体可能每个受体激活一个以上的第二个信使，或者单个第二个信使（例如，cAMP）可能激活影响许多不同通道的激酶。发散可能发生在发射机效果级联的任何阶段。

Neurotransmitters can also exhibit convergence of effects. This property means that multiple transmitters, each activating its own receptor type, converge on a single type of ion channel in a single cell. For example, some pyramidal cells of the hippocampus have GABAB, 5-HT1A, A1 (specific for adenosine), and SS (specific for somatostatin) receptors, all of which activate the same K+ channel (see Fig. 13-14B). Furthermore, in the same cells, norepinephrine, ACh, 5-HT, corticotropin-releasing hormone, and histamine all converge on and depress the slow Ca2+-activated K+ channels. Analogous to divergence, the molecular site of convergence may occur at a common second-messenger system, or different second messengers may converge on the same ion channel.

神经递质也可以表现出效果的收敛。这一特性意味着多个递质，每个递质都激活自己的受体类型，会聚在单个细胞中的单一类型的离子通道上。例如，海马体的一些锥体细胞具有 GABAB、5-HT1A、A1（对腺苷特异性）和 SS（对生长抑素特异性）受体，所有这些受体都激活相同的 K+ 通道（见图 13-14B）。此外，在同一细胞中，去甲肾上腺素、ACh、5-HT、促肾上腺皮质激素释放激素和组胺都聚集在缓慢的 Ca2+ 激活的 K+ 通道上并抑制。与发散类似，分子收敛位点可能发生在共同的第二信使系统上，或者不同的第二信使可能收敛在同一离子通道上。

Divergence and convergence can occur simultaneously within neurotransmitter systems, and many of them have chemical feedback regulation built in as well.

发散和收敛可以在神经递质系统中同时发生，其中许多系统还内置了化学反馈调节。

[编辑] 3 中枢神经系统中快氨基酸介导的突触

FAST AMINO ACID–MEDIATED SYNAPSES IN THE CNS

Fast amino acid–mediated synapses account for most of the neural activity that we associate with specific information processing in the brain: events directly responsible for sensory perception, motor control, and cognition, for example. Glutamate-mediated excitation and GABAmediated inhibition have been intensively studied. In physiological terms, these are also the best understood of the brain’s synapses, and this section describes their function.

快速氨基酸介导的突触占了我们与大脑中特定信息处理相关的大部分神经活动：例如，直接负责感觉知觉、运动控制和认知的事件。谷氨酸介导的兴奋和 GABA 介导的抑制已得到深入研究。从生理学的角度来看，这些也是对大脑突触最了解的，本节将介绍它们的功能。

As a rule, postsynaptic events are more easily measured than presynaptic events; thus, we know more about them. Of course, by measuring postsynaptic events, we also have a window onto the functions of the presynaptic terminal, and this is often the best view we can get of presynaptic functions. For this reason, we begin our description with the downstream, postsynaptic side of the synapse and then work backward to the presynaptic side.

通常，突触后事件比突触前事件更容易测量;因此，我们对他们有了更多的了解。当然，通过测量突触后事件，我们也有了一个了解突触前末梢功能的窗口，这通常是我们能得到的突触前功能的最佳视图。出于这个原因，我们从突触的下游突触后侧开始描述，然后向后到突触前侧。

[编辑] 3.1 大脑中的大多数 EPSP 由两种类型的谷氨酸门控通道介导

Most EPSPs in the brain are mediated by two types of glutamate-gated channels

Most glutamate-mediated synapses generate an EPSP with two distinct components, one much faster than the other. Both are triggered by the same presynaptic terminal releasing a single bolus of transmitter, but the two EPSP components are generated by different types of ion channels that are gated by distinct postsynaptic receptors—a case of transmitter divergence. The behavior of these channels helps in understanding the characteristics of the EPSP.

大多数谷氨酸介导的突触产生具有两个不同成分的 EPSP，一个比另一个快得多。两者都是由同一个突触前末端释放单个递质团触发的，但两个 EPSP 成分是由不同类型的离子通道产生的，这些离子通道由不同的突触后受体门控——递质发散的情况。这些通道的行为有助于了解 EPSP 的特性。

Glutamate can act on two major classes of receptors: GPCRs or metabotropic receptors, and ion channels or ionotropic receptors. As noted above, metabotropic glutamate receptors (mGluRs—the m stands for metabotropic) have seven membrane-spanning segments and are linked to heterotrimeric G proteins (Fig. 13-15A). At least eight metabotropic receptors have been identified, and comparisons of their primary structure have been used to infer the evolutionary relationships among receptor subunits (see Fig. 13-15B). The mGluRs form three groups that differ in their sequence similarity, pharmacology, and associated signaltransduction systems.

谷氨酸可以作用于两大类受体：GPCR 或代谢型受体，以及离子通道或离子型受体。如上所述，代谢型谷氨酸受体（mGluR—m 代表代谢型）有 7 个跨膜片段，并与异源三聚体 G 蛋白相连（图 13-15A）。至少已经鉴定出 8 种代谢受体，并且它们的一级结构的比较已被用于推断受体亚基之间的进化关系（见图 13-15B）。mGluR 形成三组，它们在序列相似性、药理学和相关信号转导系统方面有所不同。

The three classes of ionotropic glutamate receptors are the AMPA, NMDA, and kainate receptors (Table 13-2). By definition, each is activated by binding glutamate, but their pharmacology and functions differ. The receptor names are derived from their relatively specific agonists: AMPA stands for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. NMDA stands for N-methyl-D-aspartate. The kainate receptor is named for one of its agonists, kainic acid, and it can also be activated by domoic acid. The three ionotropic glutamate receptors can also be distinguished by their selective antagonists. AMPA and kainate receptors, but not NMDA receptors, are blocked by drugs such as CNQX (6-cyano-7-nitroquinoxaline-2,3-dione). Moreover, AMPA receptors can be specifically antagonized by 2,3-benzodiazepine derivatives, such as GYKI 53655. NMDA receptors, but not AMPA and kainate receptors, are blocked by APV (2-amino-5-phosphonovaleric acid). Selective antagonists of kainate receptors have also been discovered.

离子型谷氨酸受体的三类是 AMPA、NMDA 和 红藻氨酸 （表 13-2）。根据定义，每种物质都是通过结合谷氨酸来激活的，但它们的药理和功能不同。受体名称来源于它们相对特异性的激动剂：AMPA 代表 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸。NMDA 代表 N-甲基-D-天冬氨酸。红藻氨酸受体以其激动剂之一红藻氨酸命名，它也可以被软骨藻酸激活。三种离子型谷氨酸受体也可以通过它们的选择性拮抗剂来区分。AMPA 和红藻氨酸受体，而不是 NMDA 受体，被 CNQX（6-氰基-7-硝基喹喔啉-2,3-二酮）等药物阻断。此外，AMPA 受体可被 2,3-苯二氮卓类衍生物（如 GYKI 53655）特异性拮抗。NMDA 受体，而不是 AMPA 和红藻氨酸受体，被 APV（2-氨基-5-磷酸诺瓦乐酸）阻断。还发现了红藻氨酸受体的选择性拮抗剂。

Ionotropic glutamate receptors are constructed from ~14 different subunits. Each of these has a large extracellular glutamate-binding domain, followed by a transmembrane segment, a loop that partially enters the membrane from the cytosolic side, and then two more transmembrane segments (see Fig. 13-15C). The loop appears to line the channel pore and may be important for ion selectivity. Kinetic and structural studies indicate that the receptors are heterotetramers, with four subunits arranged around a central channel. Comparisons of primary structures can be used to infer evolutionary relationships among receptor monomeric subunits. Figure 13-15D shows a hypothesized phylogenetic tree for the three classes of ionotropic glutamate receptors, with the major subtypes clustered together. Note that the various NMDA receptor subunits (e.g., GluN1, GluN2A through GluN2D) that combine to make the NMDA receptors are more closely related to each other than to the subunits (e.g., GluK1 through GluK5) that combine to make the kainate receptors or to the subunits (e.g., GluA1 through GluA4) that combine to make the AMPA receptors. The metabotropic and ionotropic glutamate receptors have separate family trees because, although both receptor types bind glutamate, they are so different in structure that they almost certainly evolved from different ancestral protein lines.

离子型谷氨酸受体由 ~14 个不同的亚基构成。它们中的每一个都有一个大的细胞外谷氨酸结合结构域，然后是一个跨膜段，一个从胞质侧部分进入膜的环，然后是另外两个跨膜段（见图 13-15C）。该定量环似乎排列在通道孔中，可能对离子选择性很重要。动力学和结构研究表明，受体是异四聚体，有四个亚基围绕一个中央通道排列。一级结构的比较可用于推断受体单体亚基之间的进化关系。图 13-15D 显示了三类离子型谷氨酸受体的假设系统发育树，主要亚型聚集在一起。请注意，结合形成 NMDA 受体的各种 NMDA 受体亚基（例如，GluN1、GluN2A 到 GluN2D）彼此之间的关系比与结合形成红藻氨酸受体的亚基（例如，GluK1 到 GluK5）或结合形成 AMPA 受体的亚基（例如，GluA1 到 GluA4）更密切相关。代谢型和离子型谷氨酸受体具有不同的家谱，因为尽管两种受体类型都结合谷氨酸，但它们的结构差异很大，几乎可以肯定它们是从不同的祖先蛋白质系进化而来的。

As noted above, most glutamate-mediated synapses generate an EPSP with two temporal components (Fig. 13-16A, C). The two phases of the glutamate-mediated EPSP have different pharmacological profiles, kinetics, voltage dependencies, ion dependencies, and permeabilities, and most important, they serve distinct functions in the brain. Pharmacological analysis reveals that the faster phase is mediated by an AMPA-type glutamate receptor and the slower phase by an NMDA-type glutamate receptor. These glutamate-gated channels have been extensively studied with single-channel recording methods. Both AMPA and NMDA receptors have nearly equal permeability to Na+ and K+, but they differ in several ways.

如上所述，大多数谷氨酸介导的突触产生具有两个颞部分量的 EPSP（图 13-16A、C）。谷氨酸介导的 EPSP 的两个阶段具有不同的药理学特征、动力学、电压依赖性、离子依赖性和渗透性，最重要的是，它们在大脑中发挥着不同的功能。药理学分析表明，较快的阶段由 AMPA 型谷氨酸受体介导，较慢的阶段由 NMDA 型谷氨酸受体介导。这些谷氨酸门控通道已通过单通道记录方法进行了广泛研究。AMPA 和 NMDA 受体与 Na+ 和 K+ 的通透性几乎相同，但它们在几个方面有所不同。

AMPA-gated channels are found in most excitatory synapses in the brain, and they mediate fast excitation, with most types of AMPA channels normally letting very little Ca2+ into cells. Their single-channel conductance is relatively low, ~15 picosiemens (pS), and they show little voltage dependence.

AMPA 门控通道存在于大脑的大多数兴奋性突触中，它们介导快速兴奋，大多数类型的 AMPA 通道通常允许非常少的 Ca2+ 进入细胞。它们的单通道电导相对较低，为 ~15 皮秒 （pS），并且它们表现出很小的电压依赖性。

NMDA-gated channels have more complex behavior. Each has a higher conductance, ~50 pS, and much slower kinetics. The ion selectivity of NMDA channels is the key to their functions: permeability to Na+ and K+ causes depolarization and thus excitation of a cell, but their high permeability to Ca2+ allows them to influence [Ca2+]i significantly. It is difficult to overstate the importance of intracellular [Ca2+]. Ca2+ can activate many enzymes, regulate the opening of a variety of channels, and affect the expression of genes. Excess Ca2+ can even precipitate the death of a cell.

NMDA 门控通道具有更复杂的行为。每种都具有更高的电导 ~50 pS，动力学要慢得多。NMDA 通道的离子选择性是其功能的关键：对 Na+ 和 K+ 的通透性会导致去极化，从而激发细胞，但它们对 Ca2+ 的高通透性使它们能够显着影响 [Ca2+]i。细胞内 [Ca2+] 的重要性怎么强调都不为过。Ca2+ 可以激活许多酶，调节多种通道的开放，并影响基因的表达。过量的 Ca2+ 甚至会导致细胞死亡。

The gating of NMDA channels is unusual: at normal resting voltage (about −70 mV), the channel is clogged by Mg2+, and few ions pass through it; the Mg2+ pops out only when the membrane is depolarized above about −60 mV. Thus, the NMDA channel is voltage dependent in addition to being ligand gated; both glutamate and a relatively positive Vm are necessary for the channel to open. How do the NMDA-gated channels open? NMDA-gated channels coexist with AMPA-gated channels in many synapses of the brain. When the postsynaptic cell is at a relatively negative resting potential (see Fig. 13-16A, B), the glutamate released from a synaptic terminal can open the AMPA-gated channel, which is voltage independent, but not the NMDA-gated channel. However, when the postsynaptic cell is more depolarized because of the action of other synapses (see Fig. 13-16C, D), the larger depolarization of the postsynaptic membrane allows the NMDA-gated channel to open by relieving its Mg2+ block. Indeed, under natural conditions, the slower NMDA channels open only after the membrane has been sufficiently depolarized by the action of the faster AMPA channels from many simultaneously active synapses. N13-4

NMDA 通道的门控是不寻常的：在正常的静止电压（约 -70 mV）下，通道被 Mg2+ 堵塞，很少有离子通过它;只有当膜去极化高于约 −60 mV 时，Mg2+ 才会弹出。因此，NMDA 通道除了是配体门控之外，还依赖于电压;谷氨酸和相对正的 Vm 都是通道打开所必需的。NMDA 门控通道如何打开？NMDA 门控通道与大脑许多突触中的 AMPA 门控通道共存。当突触后细胞处于相对负的静息电位时（见图 13-16A、B），从突触末端释放的谷氨酸可以打开 AMPA 门控通道，该通道与电压无关，但不能打开 NMDA 门控通道。然而，当突触后细胞由于其他突触的作用而更加去极化时（见图 13-16C、D），突触后膜的较大去极化允许 NMDA 门控通道通过释放其 Mg2+ 阻滞来打开。事实上，在自然条件下，只有在膜被来自许多同时活跃的突触的较快的 AMPA 通道的作用充分去极化后，较慢的 NMDA 通道才会打开。编号 N13-4

The physiological function of kainate-gated channels is still largely a mystery, although recent evidence suggests that they may contribute to some glutamate-mediated EPSPs in specific neuron types. The kainate receptor channels also exist on presynaptic GABAergic and glutamatergic terminals, where they regulate release of the inhibitory and excitatory transmitters (i.e., GABA and glutamate).

红藻氨酸门控通道的生理功能在很大程度上仍然是一个谜，尽管最近的证据表明它们可能有助于特定神经元类型中的一些谷氨酸介导的 EPSP。红藻氨酸受体通道也存在于突触前 GABA 能和谷氨酸能末端，它们调节抑制性和兴奋性递质（即 GABA 和谷氨酸）的释放。

[编辑] 3.2 大脑中的大多数 IPSP 是由 GABAA 受体介导的，GABAA 受体被几类药物激活

Most IPSPs in the brain are mediated by the GABAA receptor, which is activated by several classes of drugs

GABA mediates the bulk of fast synaptic inhibition in the CNS, and glycine mediates most of the rest. Both the GABAA receptor and the glycine receptor are ionotropic receptors that are, in fact, Cl−-selective channels. Note that GABA can also activate the relatively common GABAB receptor, which is a GPCR or metabotropic receptor that is linked to either the opening of K+ channels or the suppression of Ca2+ channels. Finally, GABA can activate the ionotropic GABAC receptor, found primarily in neurons of the retina.

GABA 介导 CNS 中的大部分快速突触抑制，甘氨酸介导其余大部分。GABAA 受体和甘氨酸受体都是离子型受体，实际上是 Cl− 选择性通道。请注意，GABA 还可以激活相对常见的 GABAB 受体，这是一种 GPCR 或代谢受体，与 K+ 通道的开放或 Ca2+ 通道的抑制有关。最后，GABA 可以激活主要存在于视网膜神经元中的离子型 GABAC 受体。

Synaptic inhibition must be tightly regulated in the brain. Too much inhibition causes sedation, loss of consciousness, and coma, whereas too little leads to anxiety, hyperexcitability, and seizures. The need to control inhibition may explain why the GABAA receptor channel has, in addition to its GABA binding site, several other sites where chemicals can bind and thus dramatically modulate the function of the GABAA receptor channel. For example, two classes of drugs, benzodiazepines (one of which is the tranquilizer diazepam [Valium]) and barbiturates (e.g., the sedative phenobarbital), each bind to their own specific sites on the outside face of the GABAA receptor channel. By themselves, these drugs do very little to the channel’s activity. However, when GABA is around, benzodiazepines increase the frequency of channel opening, whereas barbiturates increase the duration of channel opening. In addition, the benzodiazepines can increase Cl− conductance of the GABAA receptor channel. Figure 13-17A to D shows the effects of barbiturates on both the IPSP and the single-channel currents. The result, for both the benzodiazepines and the barbiturates, is more inhibitory Cl− current, stronger IPSPs, and the behavioral consequences of enhanced inhibition.

突触抑制必须在大脑中受到严格调节。过多的抑制会导致镇静、意识丧失和昏迷，而过少会导致焦虑、过度兴奋和癫痫发作。控制抑制的需要可以解释为什么 GABAA 受体通道除了其 GABA 结合位点外，还有其他几个化学物质可以结合的位点，从而显着调节 GABAA 受体通道的功能。例如，两类药物，苯二氮卓类药物（其中一种是镇静剂地西泮 [安定]）和巴比妥类药物（例如镇静苯巴比妥），各自与 GABAA 受体通道外表面的自身特定位点结合。就其本身而言，这些药物对通道的活动作用很小。然而，当 GABA 存在时，苯二氮卓类药物会增加通道打开的频率，而巴比妥类药物会增加通道打开的持续时间。此外，苯二氮卓类药物可以增加 GABAA 受体通道的 Cl− 电导。图 13-17A 到 D 显示了巴比妥类药物对 IPSP 和单通道电流的影响。对于苯二氮卓类药物和巴比妥类药物，结果是更具抑制性的 Cl− 电流、更强的 IPSP 以及增强抑制的行为后果。

Surely, however, the GABAA receptor did not evolve specialized binding sites just for the benefit of our modern drugs. This sort of logic has motivated research to find endogenous ligands, or natural chemicals that bind to the benzodiazepine and barbiturate sites and serve as regulators of inhibition. Figure 13-17E shows some of the binding sites on the GABAA receptor. Among the potential natural modulators of the GABAA receptor may be various metabolites of the steroid hormones progesterone, corticosterone, and testosterone. Some of these hormones increase the lifetime of GABA-activated single-channel currents or the opening frequency of these channels and may thus enhance inhibition. The steroid effect is unlike the usual genomic mechanisms of steroid hormones (see pp. 71–72). Instead, steroids modulate the GABAA receptor in a manner similar to barbiturates— directly, through binding sites that are distinct from the other drug-binding sites on the GABAA receptor. Thus, these steroids are not the natural agonists of the benzodiazepine and barbiturate binding sites. The GABAA receptor is also subject to modulation by the effects of phosphorylation triggered by second-messenger signaling pathways within neurons.

然而，可以肯定的是，GABAA 受体并不是仅仅为了我们的现代药物而进化出专门的结合位点。这种逻辑促使研究寻找内源性配体，或与苯二氮卓类药物和巴比妥酸盐位点结合并作为抑制调节剂的天然化学物质。图 13-17E 显示了 GABAA 受体上的一些结合位点。GABAA 受体的潜在天然调节剂可能包括类固醇激素黄体酮、皮质酮和睾酮的各种代谢物。其中一些激素可延长 GABA 激活的单通道电流的寿命或这些通道的打开频率，从而可能增强抑制。类固醇效应与类固醇激素的通常基因组机制不同（参见第 71-72 页）。相反，类固醇以类似于巴比妥类药物的方式调节 GABAA 受体——直接通过与 GABAA 受体上的其他药物结合位点不同的结合位点。因此，这些类固醇不是苯二氮卓类药物和巴比妥类药物结合位点的天然激动剂。GABAA 受体还受到神经元内第二信使信号通路触发的磷酸化效应的调节。

[编辑] 3.3 ACh、血清素、GABA 和甘氨酸的离子型受体属于配体门控/五聚体通道超家族

The ionotropic receptors for ACh, serotonin, GABA, and glycine belong to the superfamily of ligand-gated/pentameric channels

We now know the amino-acid sequences of all major ligandgated ion channels in the brain. Even though the receptors for ACh, serotonin, GABA, and glycine are gated by such different ligands and have such different permeabilities, they have the same overall structure: five protein subunits, with each subunit being made up of four membrane-spanning segments (as shown for the GABAA receptor channel in Fig. 13-17E and inset). For example, inhibitory GABAA and glycine receptors have structures very similar to those of excitatory nicotinic ACh receptors, even though the first two are selective for anions and the last is selective for cations. For both the glycine and nicotinic ACh receptors, the transmitters bind only to the α subunits, whereas for the GABAA receptor, the transmitter GABA binds to a site at the interface of the α and β subunits.

我们现在知道大脑中所有主要配体门控离子通道的氨基酸序列。尽管 ACh、血清素、GABA 和甘氨酸的受体由如此不同的配体门控并且具有如此不同的通透性，但它们具有相同的整体结构：五个蛋白质亚基，每个亚基由四个跨膜片段组成（如图 13-17E 和插图中的 GABAA 受体通道所示）。例如，抑制性 GABAA 和甘氨酸受体的结构与兴奋性烟碱 ACh 受体的结构非常相似，尽管前两种对阴离子具有选择性，而后一种对阳离子具有选择性。对于甘氨酸和烟碱 ACh 受体，递质仅与 α 亚基结合，而对于 GABAA 受体，递质 GABA 与 α 和 β 亚基界面处的位点结合。

The primary structures of the many subunit types are remarkably similar, particularly within the amino-acid sequences of the hydrophobic membrane-spanning segments. One such stretch, called the M2 domain, tends to have repeating sequences of the polar amino acids threonine and serine. Each of the five subunits that constitute a channel contributes one M2 domain, and the set of five combines to form the water-lined pore through which ions can flow (see Fig. 13-17E). For the channels gated by GABA and glycine, selectivity for Cl− may be determined by positively charged arginines and lysines near the mouth of the pore.

许多亚基类型的一级结构非常相似，尤其是在疏水膜跨段的氨基酸序列内。其中一种称为 M2 结构域的延伸往往具有极性氨基酸苏氨酸和丝氨酸的重复序列。构成一个通道的 5 个亚基中的每一个都贡献了一个 M2 结构域，这 5 个亚基结合形成水衬里孔，离子可以流经该孔（见图 13-17E）。对于由 GABA 和甘氨酸设门的通道，Cl− 的选择性可由孔口附近带正电荷的精氨酸和赖氨酸来确定。

Not quite all ligand-gated channels belong to the same superfamily. We have already seen that the family of ionotropic glutamate receptors is distinct from the family of ligand-gated/pentameric channels. Extensive evidence also indicates that ATP is a synaptic transmitter between certain neurons and at neuron–smooth-muscle cell synapses, with rapid actions similar to those of glutamate and ACh. One of the purinergic receptors or purinoceptors, called P2X, is an ATP-gated cation channel with relatively high Ca2+ permeability. The sequence of this receptor bears little resemblance to those of either the ionotropic glutamate receptor family or the ligand-gated/pentameric channel superfamily. Instead, each subunit appears to have only two membranespanning segments, and a full channel comprises just three subunits. Functionally, the ATP-gated channel closely resembles the nicotinic ACh receptor; structurally, it is much more akin to the channel superfamily that includes voltage-gated Na+ and K+ channels (see pp. 182–183) and to some mechanosensitive channels. This similarity appears to be a case of convergent evolution among ion channels.

并非所有配体门控通道都属于同一个超家族。我们已经看到，离子型谷氨酸受体家族与配体门控/五聚体通道家族不同。大量证据还表明，ATP 是某些神经元之间和神经元-平滑肌细胞突触处的突触递质，其快速作用类似于谷氨酸和 ACh。一种嘌呤能受体或嘌呤受体，称为 P2X，是具有相对较高的 Ca2+ 通透性的 ATP 门控阳离子通道。该受体的序列与离子型谷氨酸受体家族或配体门控/五聚体通道超家族的序列几乎没有相似之处。相反，每个亚基似乎只有两个跨膜片段，而一个完整的通道仅包含三个亚基。在功能上，ATP 门控通道与烟碱型 ACh 受体非常相似;在结构上，它更类似于包括电压门控 Na+ 和 K+ 通道（参见第 182-183 页）的通道超家族和一些机械敏感通道。这种相似性似乎是离子通道之间收敛进化的一个情况。

[编辑] 3.4 大多数神经元突触在每个动作电位中释放非常少量的递质量子

Most neuronal synapses release a very small number of transmitter quanta with each action potential

A single neuromuscular junction has ~1000 active zones (see p. 210). A single presynaptic impulse releases 100 to 200 quanta of transmitter molecules (i.e., ACh), which generates an EPSP of >40 mV in the muscle cell. This is excitation with a vengeance, because the total number of quanta is far more than necessary to cause the muscle cell to fire an action potential and generate a brief contraction. Evolution has designed a neuromuscular junction that works every time, with a large margin of excess for safety. Synapses in the brain are quite different. A typical glutamatergic synapse, which has as few as one active zone, generates EPSPs of only 10 to 1000 μV. In most neurons, one EPSP is rarely enough to cause a postsynaptic cell to fire an action potential.

单个神经肌肉接头有 ~1000 个活动区（见第 210 页）。单个突触前冲动释放 100 到 200 量的递质分子（即 ACh），在肌肉细胞中产生 >40 mV 的 EPSP。这是报复性的兴奋，因为量子的总数远远超过导致肌肉细胞激发动作电位并产生短暂收缩所必需的。Evolution 设计了一种每次都能正常工作的神经肌肉接头，为了安全起见，有很大的超额余量。大脑中的突触完全不同。典型的谷氨酸能突触只有一个活动区，产生的 EPSP 仅为 10 至 1000 μV。在大多数神经元中，一个 EPSP 很少足以导致突触后细胞激发动作电位。

The basis for the small effect of central synapses has been explored by quantal analysis, with refinements of methods originally applied to the neuromuscular junction. In this approach, a single presynaptic axon is stimulated repeatedly while the postsynaptic response is recorded under voltageclamp conditions. The frequency distribution of amplitudes of excitatory postsynaptic currents (EPSCs) is analyzed, as described for the neuromuscular junction (see Fig. 8-12B). Recall that according to standard quantal theory:

通过定量分析探索了中枢突触小效应的基础，并改进了最初应用于神经肌肉接头的方法。在这种方法中，重复刺激单个突触前轴突，同时在 voltageclamp 条件下记录突触后反应。如神经肌肉接头所述，分析兴奋性突触后电流 （EPSC） 振幅的频率分布（参见图 8-12B）。回想一下，根据标准量子理论：

 m = np                               (13-1)

Here, m is the total number of quanta released, n is the maximal number of releasable quanta (perhaps equivalent to the number of active zones), and p is the average probability of release. Measurement of these parameters is very difficult. Only in rare cases in central neurons is it possible to find amplitude distributions of EPSCs with clearly separate peaks that may correspond to quantal increments of transmitter. In most cases, EPSC distributions are smooth and broad, which makes quantal analysis difficult to interpret. The analysis is hampered because EPSCs are small, it is extremely difficult to identify each small synapse, the dendrites electrically filter the recorded synaptic signals, noise arises from numerous sources (including the ion channels themselves), and synapses exhibit considerable variability. Nevertheless, what is clear is that most synaptic terminals in the CNS release only a small number of transmitter molecules per impulse, often just those contained in a single quantum (e.g., 1000 to 5000 glutamate molecules). Furthermore, the probability of release of that single quantum is often substantially less than 1; in other words, a presynaptic action potential often results in the release of no transmitter at all. When a quantum of transmitter molecules is released, only a limited number of postsynaptic receptors is available for the transmitter to bind to, usually not more than 100. In addition, because not all the receptors open their channels during each response, only 10 to 40 channels contribute current to each postsynaptic response, compared with the thousands of channels opening in concert during each neuromuscular EPSP.

这里，m 是释放的 quanta 的总数，n 是可发布 quanta 的最大数量（可能相当于活动区域的数量），p 是释放的平均概率。测量这些参数非常困难。只有在中枢神经元的极少数情况下，才有可能找到具有明显分离峰值的 EPSCs 振幅分布，这可能对应于递质的量子增量。在大多数情况下，EPSC 分布平滑而广泛，这使得量子分析难以解释。由于 EPSC 很小，识别每个小突触极其困难，树突对记录的突触信号进行电过滤，噪声来自许多来源（包括离子通道本身），并且突触表现出相当大的可变性，因此分析受到阻碍。然而，很明显的是，CNS 中的大多数突触末梢每次冲动只释放少量递质分子，通常只是单个量子中包含的那些分子（例如，1000 到 5000 个谷氨酸分子）。此外，该单个量子释放的概率通常大大小于 1;换句话说，突触前动作电位通常会导致根本没有递质的释放。当释放一定量的递质分子时，只有有限数量的突触后受体可供递质结合，通常不超过 100 个。此外，由于并非所有受体在每次反应期间都打开它们的通道，因此只有 10 到 40 个通道为每个突触后反应贡献电流，而在每个神经肌肉 EPSP 期间有数千个通道同时打开。

Because most glutamatergic synapses in the brain contribute such a weak excitatory effect, it may require the nearly simultaneous action of many synapses (and the summation of their EPSPs) to bring the postsynaptic membrane potential above the threshold for an action potential. The threshold number of synapses varies greatly among neurons, but it is roughly in the range of 10 to 100.

因为大脑中的大多数谷氨酸能突触对兴奋作用的贡献如此微弱，所以它可能需要许多突触几乎同时作用（以及它们的 EPSP 的总和）才能使突触后膜电位高于动作电位的阈值。神经元之间的突触阈值数差异很大，但大致在 10 到 100 之间。

Some exceptions to the rule of small synaptic strengths in the CNS may be noted. One of the strongest connections in the CNS is the one between the climbing fibers and Purkinje cells of the cerebellum (see Fig. 13-1B). Climbing fibers are glutamatergic axons arising from cells in the inferior olivary nucleus, and they are a critical input to the cerebellum. Climbing fibers and Purkinje cells have a dedicated, one-toone relationship. The climbing fiber branches extensively and winds intimately around each Purkinje cell, making numerous synaptic contacts. When the climbing fiber fires, it generates a massive EPSP (~40 mV, similar to the neuromuscular EPSP) that evokes a burst of spikes in the Purkinje cell. Like the neuromuscular junction, the climbing fiber–Purkinje cell relationship seems to be designed to deliver a suprathreshold response every time it is activated. It achieves this strength in the standard way: each climbing fiber makes ~200 synaptic contacts with each Purkinje cell.

可能会注意到 CNS 中小突触强度规则的一些例外。CNS 中最强的连接之一是攀爬纤维和小脑浦肯野细胞之间的连接（见图 13-1B）。攀爬纤维是起源于下橄榄核细胞的谷氨酸能轴突，它们是小脑的关键输入。攀爬纤维和浦肯野细胞具有专门的一对一关系。攀爬纤维广泛分支并紧密缠绕在每个浦肯野细胞周围，形成许多突触接触。当攀爬纤维发射时，它会产生一个巨大的 EPSP（~40 mV，类似于神经肌肉 EPSP），从而在浦肯野细胞中引起一阵尖峰。与神经肌肉接头一样，攀爬纤维-浦肯野细胞关系似乎被设计为在每次激活时提供超阈值反应。它以标准方式实现这种强度：每根攀爬纤维与每个浦肯野细胞进行 ~200 次突触接触。

[编辑] 3.5 当多个递质共定位于同一突触时，大囊泡的胞吐作用需要高频刺激

When multiple transmitters colocalize to the same synapse, the exocytosis of large vesicles requires high-frequency stimulation

As we mentioned previously, some presynaptic terminals have two or more transmitters colocalized within them. In these cases, the small transmitters are packaged into relatively small vesicles (~40 nm in diameter), whereas neuropeptides are in larger dense-core vesicles (100 to 200 nm in diameter), as noted above. This dual-packaging scheme allows the neuron some control over the relative release rates of its two types of transmitters (Fig. 13-18A). In general, low-frequency stimulation of the presynaptic terminal triggers the release of only the small transmitter (see Fig. 13-18B); co-release of both transmitters requires bursts of high-frequency stimulation (see Fig. 13-18C). This frequency sensitivity may result from the size and spatial profile of presynaptic [Ca2+]i levels achieved by the different patterns of stimulation. Presynaptic Ca2+ channels are located close to the vesicle fusion sites. Low frequencies of activation yield only localized elevations of [Ca2+]i, an amount sufficient to trigger the exocytosis of small vesicles near active zones. Larger peptide-filled vesicles are farther from active zones, and high-frequency stimulation may be necessary to achieve higher, more distributed elevations of [Ca2+]i. With this arrangement, it is obvious that the synaptic effect (resulting from the mixture of transmitters released) depends strongly on the way that the synapse is activated.

正如我们之前提到的，一些突触前末梢有两个或多个共定位的递质。在这些情况下，小递质被包装成相对较小的囊泡（直径为 ~40 nm），而神经肽则位于较大的致密核心囊泡（直径为 100 至 200 nm）中，如上所述。这种双重包装方案允许神经元对其两种递质的相对释放速率进行一些控制（图 13-18A）。一般来说，突触前末梢的低频刺激仅触发小发射器的释放（见图 13-18B）;两个发射器的共同释放需要高频刺激的爆发（见图 13-18C）。这种频率敏感性可能是由于不同刺激模式实现的突触前 [Ca2+]i 水平的大小和空间特征造成的。突触前 Ca2+ 通道位于囊泡融合位点附近。低频率的激活仅产生 [Ca2+]i 的局部升高，其量足以触发活性区附近小囊泡的胞吐作用。较大的肽填充囊泡离活动区较远，可能需要高频刺激才能实现更高、更分散的 [Ca2+]i 升高。通过这种安排，很明显突触效应（由释放的递质混合物产生）在很大程度上取决于突触被激活的方式。

[编辑] 4 中央突触的可塑性

PLASTICITY OF CENTRAL SYNAPSES

[编辑] 4.1 突触强度的使用依赖性变化是许多学习形式的基础

Use-dependent changes in synaptic strength underlie many forms of learning

Arguably the greatest achievement of a brain is its ability to learn and to store the experience and events of the past so that it is better adapted to deal with the future. Memory is the ability to store and to recall learned changes, and nervous systems without memory are extremely handicapped. Although the biological bases for learning and memory are far from understood, certain principles have become clear. First, no single mechanism can explain all forms of memory. Even within a single organism, a variety of types of memory exist—and a variety of mechanisms underlie them. Second, evidence is strong that synapses are the physical site of many if not most forms of memory storage in the brain. As the major points of interaction between neurons, synapses are well placed to alter the processing capabilities of a neural circuit in interesting and useful ways. Third, the synaptic strength (i.e., the mean amplitude of the postsynaptic response) of many synapses may depend on their previous activity. The sensitivity of a synapse to its past activity can lead to a long-term change in its future effectiveness, which is all we need to build memory into a neural circuit.

可以说，大脑最大的成就是它能够学习和存储过去的经验和事件，以便更好地适应未来。记忆是存储和回忆习得的变化的能力，没有记忆的神经系统是极度残疾的。尽管学习和记忆的生物学基础还远未被理解，但某些原则已经变得清晰。首先，没有一种机制可以解释所有形式的记忆。即使在单个生物体中，也存在各种类型的记忆，并且它们的基础是各种机制。其次，有强有力的证据表明，突触是大脑中许多（如果不是大多数）形式的记忆存储的物理场所。作为神经元之间相互作用的主要点，突触可以很好地以有趣和有用的方式改变神经回路的处理能力。第三，许多突触的突触强度（即突触后反应的平均振幅）可能取决于它们以前的活动。突触对其过去活动的敏感性会导致其未来有效性的长期变化，这就是我们将记忆构建到神经回路中所需要的一切。

Some forms of memory last just a few seconds or minutes, only to be lost or replaced by new memories. Working memory is an example. It is the continual series of fleeting memories that we use during the course of a day to remember facts and events, what was just spoken to us, where we put the phone down, whether we are coming or going— things that are useful for the moment but need not be stored longer. Other forms of memory may last for hours to decades and strongly resist disruption and replacement. Such longterm memory allows the accumulation of knowledge over a lifetime. Some memories may be formed after only a single trial (recall a particularly dramatic but unique event in your life), whereas others form only with repeated practice (examples include speaking a language or playing a guitar). Detailed descriptions of the many types of memory are beyond the scope of this chapter, but it seems obvious that no single synaptic mechanism would suffice to generate all of them. Neurophysiologists have identified many types of synaptic plasticity, the term for activity-dependent changes in the effectiveness of synapses, and some of their mechanisms are well understood. However, it has been very difficult to demonstrate that specific forms of memory use particular types of synaptic plasticity, and correlation of memory with synaptic plasticity remains a coveted goal of current research.

某些形式的记忆只持续几秒钟或几分钟，然后就会丢失或被新的记忆所取代。工作内存就是一个例子。它是我们在一天中用来记住事实和事件、刚刚对我们说的话、我们放下电话的地方、我们是来还是走——这些东西在当下有用，但不需要存储更长时间。其他形式的记忆可能会持续数小时到数十年，并且强烈抵抗中断和替换。这种长期记忆允许在一生中积累知识。有些记忆可能仅在一次尝试后形成（回想一下您生活中特别戏剧性但独特的事件），而另一些记忆则仅通过反复练习形成（例如说一种语言或弹吉他）。对许多类型的记忆的详细描述超出了本章的范围，但似乎很明显，没有单一的突触机制足以产生所有这些记忆。神经生理学家已经确定了许多类型的突触可塑性，突触可塑性是指突触有效性的活动依赖性变化，它们的一些机制已得到很好的理解。然而，要证明特定形式的记忆使用特定类型的突触可塑性是非常困难的，并且记忆与突触可塑性的相关性仍然是当前研究令人垂涎的目标。

[编辑] 4.2 短期突触可塑性通常反映突触前变化

Short-term synaptic plasticity usually reflects presynaptic changes

Repetitive stimulation of neuronal synapses often yields brief periods of increased or decreased synaptic strength (Fig. 13-19). The usual nomenclature for the short-term increases in strength is facilitation (which lasts tens to hundreds of milliseconds), augmentation (which lasts several seconds), and post-tetanic potentiation (which lasts tens of seconds to several minutes and outlasts the period of highfrequency stimulation). Not all of them are expressed at every type of synapse. In general, the longer-lasting modifications require longer periods of conditioning stimuli. Shortterm decreases in synaptic strength include depression, which can occur during high-frequency stimulation, and habituation, which is a slowly progressing decrease that occurs during relatively low-frequency activation.

神经元突触的重复刺激通常会导致突触强度短暂增加或降低（图 13-19）。短期强度增加的通常术语是促进（持续数十到数百毫秒）、增强（持续几秒钟）和破伤风后增强（持续数十秒到几分钟，持续时间超过高频刺激期）。并非所有它们都在每种类型的突触中表达。一般来说，更持久的修改需要更长的条件刺激时间。突触强度的短期下降包括抑郁（可能在高频刺激期间发生）和习惯化（在相对低频激活期间发生的缓慢进展的下降）。

Three potential explanations may be offered for shortterm increases in synaptic strength. First, the presynaptic terminal may release more transmitter in response to each action potential. Second, the postsynaptic receptors may be more responsive to transmitter because of a change in their number or sensitivity. Third, both of these changes may occur simultaneously. Studies involving a variety of synapses suggest that the first explanation is most often correct. In these cases, quantal analysis usually shows that synapses become stronger because more neurotransmitter is released during each presynaptic action potential; postsynaptic mechanisms generally do not play a role. This form of plasticity seems to depend on the influx of presynaptic Ca2+ during the conditioning tetanus. N13-5 Katz and Miledi first proposed that synaptic strength is increased because of residual Ca2+ left in the terminal after a conditioning train of stimuli at the neuromuscular junction. Recent work supports this hypothesis. The idea is that (1) a tetanic stimulus leads to a substantial increase in presynaptic [Ca2+]i that saturates intracellular Ca2+ buffers; (2) the high presynaptic [Ca2+]i takes a relatively long time to decline to baseline, and prolonged stimulation requires prolonged recovery times; and (3) presynaptic action potentials arriving after the conditioning tetanus generate a Ca2+ influx that sums with the residual [Ca2+]i from the preceding tetanus to yield a larger than normal peak [Ca2+]i. Because the dependence of transmitter release on presynaptic [Ca2+]i is highly nonlinear, the increase in release after conditioning stimuli can be large. Several types of Ca2+-sensitive proteins are present in the presynaptic terminal; the Ca2+ binding site on synaptotagmin triggers exocytosis, whereas Ca2+ binding sites on other proteins— perhaps including protein kinase C (see pp. 60–61) and Ca2+- calmodulin–dependent protein kinases (CaMKs; see p. 60) regulate short-term increases in transmitter release.

突触强度的短期增加可能提供三种可能的解释。首先，突触前末梢可能会释放更多的发射器以响应每个动作电位。其次，突触后受体可能对递质更敏感，因为它们的数量或敏感性发生了变化。第三，这两种变化可能同时发生。涉及各种突触的研究表明，第一种解释通常是正确的。在这些情况下，量化分析通常表明突触变得更强，因为在每个突触前动作电位期间释放了更多的神经递质;突触后机制通常不起作用。这种形式的可塑性似乎取决于预处理破伤风期间突触前 Ca2+ 的流入。N13-5 Katz 和 Miledi 首次提出，突触强度增加是因为在神经肌肉接头处进行一系列刺激的预处理后，残留的 Ca2+ 留在末端。最近的工作支持这一假设。这个想法是 （1） 破伤风刺激导致突触前 [Ca2+]i 的显着增加，使细胞内的 Ca2+ 缓冲液饱和;（2） 高突触前 [Ca2+]i 需要相对较长的时间才能下降到基线，长时间的刺激需要更长的恢复时间;（3） 预处理破伤风后到达的突触前动作电位产生 Ca2+ 内流，该内流与前一破伤风的残余 [Ca2+]i 相加，产生大于正常峰值 [Ca2+]i。由于递质释放对突触前 [Ca2+]i 的依赖性是高度非线性的，因此调节刺激后释放的增加可能很大。突触前末梢存在几种类型的 Ca2+ 敏感蛋白;突触结合蛋白上的 Ca2+ 结合位点触发胞吐作用，而其他蛋白质上的 Ca2+ 结合位点——可能包括蛋白激酶 C（见第 60-61 页）和 Ca2+-钙调蛋白依赖性蛋白激酶 （CaMKs;见第 60 页）调节递质释放的短期增加。

Several mechanisms cause short-term decreases in synaptic strength, including the depletion of vesicles and the inactivation of presynaptic Ca2+ channels. Habituation has been studied in the marine invertebrate Aplysia. The animal reflexively withdraws its gill in response to a stimulus to its skin. Vincent Castellucci and Eric Kandel N13-6 found that withdrawal becomes less vigorous—that is, the animal habituates—when the stimulus is presented repeatedly. The basis for this behavioral habituation is, at least in part, a decrease in the strength of synapses made by skin sensory neurons onto gill-withdrawal motor neurons. Using quantal analysis, Castellucci and Kandel showed that synaptic habituation is due to fewer transmitter quanta being released per action potential. Thus, as with the short-term enhancements of synaptic strength, this example of habituation is due to presynaptic modifications.

几种机制会导致突触强度的短期降低，包括囊泡的耗竭和突触前 Ca2+ 通道的失活。已经在海洋无脊椎动物 Aplysia 中研究了习惯化。动物反射性地抽出鳃以响应对其皮肤的刺激。Vincent Castellucci 和 Eric Kandel N13-6 发现，当刺激反复出现时，退缩变得不那么剧烈——也就是说，动物会习惯化。这种行为习惯化的基础至少部分是皮肤感觉神经元对鳃撤退运动神经元的突触强度降低。使用量子分析，Castellucci 和 Kandel 表明突触习惯化是由于每个动作电位释放的递质量子较少。因此，与突触强度的短期增强一样，这种习惯化的例子是由于突触前修饰。

[编辑] 4.3 海马体中的长期增强可能持续数天或数周

Long-term potentiation in the hippocampus may last for days or weeks

In 1973, Timothy Bliss and Terje Lømo described a form of synaptic enhancement that lasted for days or even weeks. This phenomenon, now called long-term potentiation (LTP), occurred in excitatory synapses of the mammalian cerebral cortex. LTP was generated by trains of highfrequency stimulation applied to the presynaptic axons, and it was expressed as an increase in the size of EPSPs. Several properties of LTP, including its longevity and its location in cortical synapses, made it immediately attractive as a candidate for the cellular basis of certain forms of vertebrate learning. Years of intensive research have revealed many details of the molecular mechanisms of LTP. They have also provided some evidence, albeit still indirect, that LTP is involved in some forms of learning. Numerous mechanistically distinct types of LTP exist; here we discuss only the best-studied example.

1973 年，Timothy Bliss 和 Terje Lømo 描述了一种持续数天甚至数周的突触增强形式。这种现象现在称为长时程增强 （LTP），发生在哺乳动物大脑皮层的兴奋性突触中。LTP 是通过对突触前轴突施加一系列高频刺激产生的，它表示为 EPSP 大小的增加。LTP 的几个特性，包括它的长寿和它在皮质突触中的位置，使其立即成为某些形式的脊椎动物学习的细胞基础的候选者。多年的深入研究揭示了 LTP 分子机制的许多细节。他们还提供了一些证据，尽管仍然是间接的，表明 LTP 参与了某些形式的学习。存在许多机制上不同的 LTP 类型;在这里，我们只讨论研究得最好的例子。

LTP is easily demonstrated in several synaptic relays within the hippocampus, a part of the cerebral cortex that has often been considered essential for the formation of certain long-term memories. The best studied of these synapses is between the Schaffer collateral axons of CA3 pyramidal neurons (forming the presynaptic terminals) and CA1 pyramidal neurons (the postsynaptic neurons). In a typical experiment, the strength of synapses to the CA1 neuron is tested by giving a single shock about once every 10 seconds. Stimuli are applied separately to two sets of Schaffer collateral axons that form two different sets of synapses (Fig. 13-20A). If we stimulate a “control” Schaffer collateral once every 10 seconds, the amplitude of the EPSPs recorded in the postsynaptic CA1 neuron remains rather constant during many tens of minutes (see Fig. 13-20B). However, if we pair the presynaptic test shocks occurring once every 10 seconds to the “test” pathway with simultaneous postsynaptic depolarization of the CA1 neuron, the amplitude of the EPSP gradually increases several-fold (see Fig. 13-20C), which is indicative of LTP. In this case, the trigger for LTP was the pairing of a low-frequency presynaptic input and a strong postsynaptic depolarization. We already saw that Bliss and Lømo originally induced LTP by activating the presynaptic axons with brief bursts of tetanic stimulation (50 to 100 stimuli at a frequency of ~100 Hz). Both strategies— presynaptic-postsynaptic pairing protocol and tetanic presynaptic stimulation—are effective ways to induce LTP.

LTP 很容易在海马体内的几个突触中继中得到证明，海马是大脑皮层的一部分，通常被认为对某些长期记忆的形成至关重要。对这些突触研究得最好的是 CA3 锥体神经元（形成突触前末端）和 CA1 锥体神经元（突触后神经元）的 Schaffer 侧支轴突之间。在典型的实验中，通过大约每 10 秒进行一次电击来测试 CA1 神经元突触的强度。刺激分别施加到两组 Schaffer 侧支轴突上，这些轴突形成两组不同的突触（图 13-20A）。如果我们每 10 秒刺激一次“对照”Schaffer 侧支，突触后 CA1 神经元中记录的 EPSP 的振幅在数十分钟内保持相当恒定（见图 13-20B）。然而，如果我们将每 10 秒发生一次的突触前测试休克与“测试”通路同时进行突触后去极化配对，EPSP 的振幅会逐渐增加几倍（见图 13-20C），这表明 LTP。在这种情况下，LTP 的触发因素是低频突触前输入和强突触后去极化的配对。我们已经看到，Bliss 和 Lømo 最初是通过短暂的破伤风刺激（50 到 100 次刺激，频率为 ~100 Hz）激活突触前轴突来诱导 LTP。两种策略——突触前-突触后配对方案和强直性突触前刺激——都是诱导 LTP 的有效方法。

The induction of LTP has several interesting features that enhance its candidacy as a memory mechanism. First, it is input specific, which means that only the activated set of synapses onto a particular cell will be potentiated, whereas unactivated synapses to that same neuron remain unpotentiated. Second, induction of LTP requires coincident activity of the presynaptic terminals plus significant depolarization of the postsynaptic membrane. We saw this effect in Figure 13-20C, which showed that inducing LTP required coincident synaptic input and depolarization. Because single hippocampal synapses are quite weak, the requirement for substantial postsynaptic activation means that LTP is best induced in an in vivo situation by cooperativity—enough presynaptic axons must cooperate, or fire coincidentally, to strongly activate the postsynaptic cell. The cooperative property of LTP can be used to form associations between synaptic inputs. Imagine that two sets of weak inputs onto one cell are, by themselves, too weak to induce LTP. Perhaps each encodes some sensory feature of an object: the sight (input 1) and sound (input 2) of your pet cat. If the two firing together are strong enough to induce LTP, both sets of synaptic inputs will tend to strengthen, and the features that they encode (the sight and sound of the cat) will become associated in their enhanced ability to fire the postsynaptic cell. In contrast, for example, the sight of your cat and the sound of your alarm clock will rarely occur together, and their neural equivalents will not become associated.

LTP 的归纳有几个有趣的特征，增强了它作为一种记忆机制的候选资格。首先，它是特定于输入的，这意味着只有特定细胞上激活的突触集才会被增强，而同一神经元的未激活突触则保持未增强。其次，LTP 的诱导需要突触前末梢的重合活性以及突触后膜的显着去极化。我们在图 13-20C 中看到了这种效果，它表明诱导 LTP 需要重合突触输入和去极化。由于单个海马突触非常弱，因此需要大量突触后激活意味着 LTP 最好在体内情况下通过协同性诱导——足够的突触前轴突必须配合或巧合地触发，以强烈激活突触后细胞。LTP 的协作特性可用于在突触输入之间形成关联。想象一下，一个单元的两组弱输入本身就太弱而无法诱导 LTP。也许每个都编码了一个物体的某种感官特征：你的宠物猫的视觉（输入 1）和声音（输入 2）。如果两者一起放电的强度足以诱导 LTP，则两组突触输入都将趋于增强，并且它们编码的特征（猫的视觉和声音）将与它们激发突触后细胞的增强能力相关联。相比之下，例如，你的猫的景象和闹钟的声音很少会同时出现，它们的神经等价物也不会关联起来。

The molecular mechanisms of one form of LTP in the CA1 region of hippocampus have been partially elucidated. The synapse uses glutamate as its transmitter, and both AMPA and NMDA receptors are activated to generate an EPSP. Induction of this type of LTP depends on an increase in postsynaptic [Ca2+]i levels beyond a critical level and lasting for about 1 to 2 seconds. (Recall that the short-term forms of enhancement required a presynaptic increase in [Ca2+]i; see the preceding section.) Under most conditions, postsynaptic [Ca2+]i levels rise during a tetanic stimulus because of the activation of NMDA receptors, the only type of glutamate-activated channel that is usually permeable to Ca2+ (see Fig. 13-16). Recall also that the NMDA-type glutamate receptor channel is voltage dependent; to open, it requires Vm to be relatively positive. The cooperativity requirement of LTP is really a requirement for the activation of NMDA receptors so that Ca2+ can enter—if the postsynaptic Vm is too negative (as it is when synaptic activation is weak), NMDA channels remain mostly closed. If activation is strong (as it is when multiple inputs cooperate or when tetanus occurs), Vm becomes positive enough to allow NMDA channels to open. The stimulus-induced rise in postsynaptic [Ca2+]i activates at least one essential kinase: CaMKII (see p. 60). Blocking this kinase with drugs prevents induction of LTP. Several other types of kinases are implicated, but the evidence that these mediate—as opposed to modulate—LTP is equivocal.

海马 CA1 区一种形式的 LTP 的分子机制已被部分阐明。突触使用谷氨酸作为其递质，AMPA 和 NMDA 受体都被激活以产生 EPSP。这种类型的 LTP 的诱导取决于突触后 [Ca2+]i 水平的增加超过临界水平并持续约 1 至 2 秒。（回想一下，短期形式的增强需要 [Ca2+]i 的突触前增加;见上一节。在大多数情况下，突触后 [Ca2+]i 水平在强直性刺激期间升高，因为 NMDA 受体被激活，NMDA 受体是唯一一种通常对 Ca2+ 具有渗透性的谷氨酸激活通道（见图 13-16）。还记得 NMDA 型谷氨酸受体通道是电压依赖性的;要打开，它要求 Vm 相对正。LTP 的协同性要求实际上是激活 NMDA 受体的要求，以便 Ca2+ 可以进入——如果突触后 Vm 太负（就像突触激活较弱时一样），NMDA 通道大部分保持闭合。如果激活很强（如当多个输入合作或发生破伤风时），Vm 变得足够正，允许 NMDA 通道打开。刺激诱导的突触后 [Ca2+]i 升高激活至少一种必需激酶：CaMKII（见第 60 页）。用药物阻断这种激酶可防止 LTP 的诱导。涉及其他几种类型的激酶，但这些激酶介导而不是调节 LTP 的证据是模棱两可的。

The molecular pathways leading to the expression and maintenance of LTP are more obscure after the Ca2+-induced activation of CaMKII. Evidence has been presented both for and against postsynaptic and presynaptic changes as explaining the increase in synaptic strength. For the most commonly studied form of LTP described here (i.e., dependent on NMDA receptors), compelling evidence demonstrates a postsynaptic mechanism involving the recruitment of more AMPA receptors to the postsynaptic membrane. Sometimes, postsynaptic AMPA receptors appear to be functionally “silent” until LTP mechanisms activate them or insert them into the membrane. Evidence also suggests a presynaptic mechanism for enhancing transmitter release. This presynaptic hypothesis requires the presence of some unknown, rapidly diffusing retrograde messenger that can carry a signal from the postsynaptic side (where rising [Ca2+]i is clearly a trigger for LTP) back to the presynaptic terminal.

在 Ca2+ 诱导的 CaMKII 激活后，导致 LTP 表达和维持的分子途径更加模糊。已经提出了支持和反对突触后和突触前变化的证据，以解释突触强度的增加。对于此处描述的最常见研究的 LTP 形式（即依赖于 NMDA 受体），令人信服的证据表明突触后机制涉及将更多的 AMPA 受体募集到突触后膜。有时，突触后 AMPA 受体在功能上似乎是“沉默的”，直到 LTP 机制激活它们或将它们插入膜中。证据还表明，一种增强递质释放的突触前机制。这种突触前假说需要存在一些未知的、快速扩散的逆行信使，该信使可以将信号从突触后侧（其中上升的 [Ca2+]i 显然是 LTP 的触发因素）带回突触前末梢。

[编辑] 4.4 长期抑郁症有多种形式

Long-term depression exists in multiple forms

Memory systems may have mechanisms not only to increase synaptic strength but also to decrease it. In fact, long-term depression (LTD) can be induced in the same synapses within the hippocampus that generate the [Ca2+]i-dependent LTP described in the preceding section. The critical feature that determines whether the synapses will strengthen or weaken is simply the frequency of stimulation that they receive. For example, several hundred stimuli delivered at 50 Hz produce LTP, the same number delivered at 10 Hz has little effect, and at 1 Hz they produce LTD. One set of synapses can be strengthened or weakened repeatedly, which suggests that each process (LTP and LTD) acts on the same molecular component of the synapses. LTD induced in this way shows the same input specificity as LTP—only the stimulated synapses onto a cell are depressed.

记忆系统可能不仅具有增加突触强度的机制，而且还具有降低突触强度的机制。事实上，长期抑郁 （LTD） 可以在海马体内产生上一节中描述的 [Ca2+]i 依赖性 LTP 的相同突触中诱导。决定突触是加强还是减弱的关键特征只是它们接受的刺激频率。例如，以 50 Hz 传递的数百个刺激产生 LTP，以 10 Hz 传递的相同数量的刺激影响很小，而在 1 Hz 时它们产生 LTD。一组突触可以反复加强或减弱，这表明每个过程（LTP 和 LTD）都作用于突触的相同分子成分。以这种方式诱导的 LTD 显示出与 LTP 相同的输入特异性——只有细胞上受刺激的突触被抑制。

Multiple forms of LTD differ according to their molecular mechanisms. One type depends on activation of mGluRs; another apparently requires activation of cannabinoid receptors. We describe the type of LTD that has been studied most extensively. The induction requirements of this form of hippocampal LTD are paradoxically similar to those of LTP: LTD induced by low-frequency stimulation depends on the activation of NMDA receptors, and it requires an increase in postsynaptic [Ca2+]i. The key determinant of whether a tetanic stimulus induces LTP or LTD may be the level to which postsynaptic [Ca2+]i rises. Figure 13-21 illustrates a simple model of the induction mechanisms for LTD and LTP. Synaptic activation releases glutamate, which activates NMDA receptors, which in turn allow Ca2+ to enter the postsynaptic cell. In the case of high-frequency stimulation, postsynaptic [Ca2+]i rises to very high levels; if stimulation is of low frequency, the rise in postsynaptic [Ca2+]i is more modest. High levels of [Ca2+]i lead to a net activation of protein kinases, whereas modest levels of [Ca2+]i preferentially activate protein phosphatases, perhaps calcineurin. The kinases and phosphatases in turn act on synaptic proteins or phosphoproteins that somehow regulate synaptic strength.

LTD 的多种形式根据其分子机制而有所不同。一种类型依赖于 mGluR 的激活;另一种显然需要激活大麻素受体。我们描述了研究最广泛 LTD 的类型。这种形式的海马 LTD 的诱导要求与 LTP 的诱导要求自相矛盾地相似：低频刺激诱导的 LTD 取决于 NMDA 受体的激活，并且需要突触后 [Ca2+]i 的增加。破伤风刺激是否诱导 LTP 或 LTD 的关键决定因素可能是突触后 [Ca2+]i 升高的水平。图 13-21 说明了 LTD 和 LTP 的感应机制的简单模型。突触激活释放谷氨酸，谷氨酸激活 NMDA 受体，进而允许 Ca2+ 进入突触后细胞。在高频刺激的情况下，突触后 [Ca2+]i 上升到非常高的水平;如果刺激频率较低，则突触后 [Ca2+]i 的上升较为温和。高水平的 [Ca2+]i 导致蛋白激酶的净激活，而适度水平的 [Ca2+]i 优先激活蛋白质磷酸酶，可能是钙调磷酸酶。激酶和磷酸酶反过来作用于突触蛋白或磷蛋白，它们以某种方式调节突触强度。

LTP-inducing stimuli phosphorylate specific residues on AMPA receptors and, conversely, dephosphorylate other residues on AMPA receptors. These post-translational changes are, however, only part of the story of long-term synaptic plasticity. LTP increases—and LTD decreases—the numbers of AMPA receptors in the postsynaptic membrane by modulating receptor trafficking into and out of the surface membrane. Longer lasting LTP- and LTD-induced changes seem to involve mechanisms that depend on protein synthesis, including structural changes in synapses and spines.

LTP 诱导刺激 AMPA 受体上的特异性残基磷酸化，反之，使 AMPA 受体上的其他残基去磷酸化。然而，这些翻译后的变化只是长期突触可塑性故事的一部分。LTP 通过调节受体进出表面膜的运输来增加突触后膜中 AMPA 受体的数量，而 LTD 减少突触后膜中 AMPA 受体的数量。LTP 和 LTD 诱导的更持久的变化似乎涉及依赖于蛋白质合成的机制，包括突触和脊柱的结构变化。

The simple scheme in Figure 13-21 leaves unidentified many of the steps between the rise in postsynaptic [Ca2+]i and the change in synaptic strength; most of the molecular details remain to be determined. However, if the model is correct, it means that synaptic strength (and, by implication, some memory) is under the dynamic control of cellular processes that determine postsynaptic [Ca2+]i. Once again in physiology, [Ca2+]i has been assigned a pivotal role in a vital process.

图 13-21 中的简单方案留下了突触后 [Ca2+]i 升高和突触强度变化之间的许多步骤未确定;大多数分子细节仍有待确定。然而，如果模型是正确的，则意味着突触强度（以及暗示的一些记忆）受到决定突触后 [Ca2+]i 的细胞过程的动态控制。再一次在生理学中，[Ca2+]i 在一个重要过程中被赋予了关键作用。

[编辑] 4.5 小脑长期抑郁可能对运动学习很重要

Long-term depression in the cerebellum may be important for motor learning

A variety of other types of LTP and LTD have been described in other synapses and even within the same synapses of the CA1 region in the hippocampus. Clearly, multiple means and mechanisms may be used to strengthen and to weaken synapses in the brain over a range of time courses. We briefly describe one other well-studied type of synaptic modification in the mammalian brain, LTD in the cerebellum.

其他几种类型的 LTP 和 LTD 已在其他突触中被描述，甚至在海马 CA1 区域的同一突触内。显然，可以使用多种方法和机制在一系列时间过程中加强和减弱大脑中的突触。我们简要描述了哺乳动物大脑中另一种经过充分研究的突触修饰类型，即小脑中的 LTD。

The cerebellum is a large brain structure that is important in motor control and strongly implicated in motor learning. The cortex of the cerebellum is a thin, multiply folded sheet of cells with an intricate but highly repetitious neural structure. The principal cell of the cerebellum is the Purkinje cell, a large neuron that uses GABA as its transmitter and whose axon forms the sole output of the cerebellar cortex. Purkinje cells receive two types of excitatory synaptic input: (1) each Purkinje cell receives powerful synaptic contact from just a single climbing fiber, which comes from a cell in the inferior olivary nucleus (see Fig. 13-1B), and (2) each Purkinje cell also receives synaptic input from ~150,000 parallel fibers, which originate from the tiny granule cells of the cerebellum itself. This remarkable conjunction of synaptic inputs is the basis for a theory of motor learning that was proposed by David Marr and James Albus in 1970. They predicted that the parallel-fiber synapses should change their strength only if they are active at the same time as the climbing fiber onto the same cell. This idea received important experimental support from the laboratory of Masao Ito.

小脑是一个大型大脑结构，在运动控制中很重要，与运动学习密切相关。小脑皮层是一片薄的、多折叠的细胞片，具有复杂但高度重复的神经结构。小脑的主要细胞是浦肯野细胞，这是一个使用 GABA 作为其递质的大神经元，其轴突形成小脑皮层的唯一输出。浦肯野细胞接收两种类型的兴奋性突触输入：（1） 每个浦肯野细胞仅从一根攀爬纤维接收强大的突触接触，该纤维来自下橄榄核中的细胞（见图 13-1B），以及 （2） 每个浦肯野细胞还接收来自 ~150,000 根平行纤维的突触输入，这些纤维来自小脑本身的微小颗粒细胞。突触输入的这种显着结合是 David Marr 和 James Albus 于 1970 年提出的运动学习理论的基础。他们预测，只有当平行纤维突触与攀爬纤维同时活跃到同一细胞上时，它们才会改变其强度。这个想法得到了 Masao Ito 实验室的重要实验支持。

Ito and colleagues monitored EPSPs in a Purkinje cell while stimulating some of its inputs from parallel fibers and its single input from the climbing fiber. They found that the EPSPs generated by the parallel fibers became smaller when both the parallel fibers and the cell’s climbing fiber were coactivated at low frequencies. Stimulating either input alone did not cause any change. Cerebellar LTD can last at least several hours. As with the hippocampal LTP and LTD described above, cerebellar LTD showed input specificity: only those parallel fibers coactivated with the climbing fiber were depressed, whereas others with synapses onto the cell were unchanged.

Ito 及其同事监测了浦肯野电池中的 EPSP，同时刺激来自平行纤维的一些输入和来自攀爬纤维的单个输入。他们发现，当平行纤维和细胞的攀爬纤维在低频下共激活时，平行纤维产生的 EPSP 变得更小。单独刺激任何一种输入都不会引起任何变化。Cerebellar LTD 可以持续至少几个小时。与上述海马 LTP 和 LTD 一样，小脑 LTD 显示出输入特异性：只有那些与攀爬纤维共激活的平行纤维被抑制，而其他具有突触到细胞上的纤维保持不变。

The mechanism of cerebellar LTD has some similarities to that of LTD in the hippocampus, but it is also distinctly different. Parallel-fiber synapses weaken because of reduced effectiveness—a reduction in either number or sensitivity— of postsynaptic AMPA-type glutamate receptors. As in the hippocampus, induction of cerebellar LTD requires an increase in postsynaptic [Ca2+]i. However, unlike in the hippocampus, no NMDA-type glutamate receptors are present in the mature cerebellum to mediate Ca2+ flux. Instead, Ca2+ can enter Purkinje cells through voltage-gated Ca2+ channels that are opened during the exceptionally powerful EPSP that the climbing fiber generates. In addition to a rise in postsynaptic [Ca2+]i, cerebellar LTD induction seems to require the activation of mGluRs and protein kinase C by the parallel fibers. Increases in postsynaptic [Na+]i and NO have also been implicated in LTD induction. At present, the relationships between these putative induction factors and the molecular pathways leading to the expression of cerebellar LTD are obscure.

小脑 LTD 的机制与海马体的 LTD 有一些相似之处，但也明显不同。平行纤维突触减弱是由于突触后 AMPA 型谷氨酸受体的有效性降低——数量或敏感性降低。与海马体一样，小脑 LTD 的诱导需要突触后 [Ca2+]i 的增加。然而，与海马体不同，成熟小脑中不存在 NMDA 型谷氨酸受体来介导 Ca2+ 通量。相反，Ca2+ 可以通过电压门控 Ca2+ 通道进入浦肯野细胞，这些通道在攀爬纤维产生的异常强大的 EPSP 期间打开。除了突触后 [Ca2+]i 的增加外，小脑 LTD 诱导似乎还需要平行纤维激活 mGluR 和蛋白激酶 C。突触后 [Na+]i 和 NO 的增加也与 LTD 诱导有关。目前，这些推定的诱导因子与导致小脑 LTD 表达的分子途径之间的关系尚不清楚。

As we pointed out for the hippocampus, most efficient memory systems need mechanisms for both weakening and strengthening of their synapses. It turns out that parallelfiber synapses of the cerebellum can be induced to generate LTP as well as LTD by stimulating them at relatively low frequencies (2 to 8 Hz). Cerebellar LTP, unlike hippocampal LTP, requires presynaptic but not postsynaptic increases in [Ca2+]i. Potentiation seems to be a result of increased transmitter release from the presynaptic terminal.

正如我们为海马体指出的那样，最有效的记忆系统需要削弱和加强其突触的机制。事实证明，可以通过以相对较低的频率（2 至 8 Hz）刺激小脑的平行纤维突触来诱导它们产生 LTP 和 LTD。与海马 LTP 不同，小脑 LTP 需要突触前增加，但不需要突触后 [Ca2+]i 增加。增强似乎是突触前末梢递质释放增加的结果。

[编辑] 5 Reference

• Physiology
• Pharmacology
• Addiction
• BBB 血脑屏障概述

• Smith et al. Insights into inner ear function and disease through novel visualizatio of the ductus reuniens, a semila communication between hearing and balance mechanisms. JARO (2022)
• http://www.cochlea.eu/en/cochlea
• http://www.cochlea.eu/en/cochlea/cochlear-fluids