Ch13 Synaptic Transmission in the nervous system

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。

1 Neuronal Synapses（神经元突触）

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）。

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

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

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

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。

2 Reference

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