Neurons and Synapses · 7	1

Fig. 1.5 Synaptic structure (schematic drawing). 1, Presynaptic membrane with gridlike thickening, leaving hexagonal spaces in between. 2, Synaptic cleft. 3, Postsynaptic membrane. 4, Synaptic vesicle. 5, Fusion of a synaptic vesicle with the presynaptic membrane (so-called Ω [omega] figure), with release of the neurotransmitter (green) into the synaptic cleft. 6, Vesicle with neurotransmitter molecules taken back up into the terminal bouton. 7, Axon filaments. From: Kahle W and Frotscher M: Taschenatlas der Anatomie, vol. 3, 8th ed., Thieme, Stuttgart, 2002.

these classes are also designated by the letters A, B, and C. The thickly myelinated A fibers are of 3­20 μm diameter and conduct at speeds up to 120 m/s. The thinly myelinated B fibers are up to 3 μm thick and conduct at speeds up to 15 m/s. The unmyelinated C fibers conduct no faster than 2 m/s.

Synapses

General structure. As late as the 1950s, it was still unclear whether neurons were connected to each other in a continuous network (syncytium), which would theoretically allow rapid electrical communication between neurons, or whether each neuron was entirely enclosed in its own membrane. Subsequent

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18 · 1 Elements of the Nervous System

visualization of synapses under the electron microscope settled the question: there is no direct spatial continuity between neurons. The axon ends on one side of the synapse, and neural impulses are conveyed across it by special transmitter substances (Fig. 1.5). The axon terminal (bouton) is the presynaptic part of the synapse, and the membrane of the cell receiving the transmitted information is the postsynaptic part. The presynaptic and postsynaptic membranes are separated by the synaptic cleft. The bouton contains vesicles filled with the neurotransmitter substance.

Examination of synapses under the electron microscope reveals specialized, osmiophilic thickenings of the presynaptic and postsynaptic membranes, which are more pronounced on the postsynaptic side in so-called asymmetrical synapses, and are approximately equally thick on both sides in so-called symmetrical synapses. These two types of synapse are also known, after their original describer, as Gray type I and Gray type II synapses, respectively. Asymmetrical synapses were found to be excitatory and symmetrical synapses to be inhibitory (see below for the concepts of excitation and inhibition). This hypothesis was later confirmed by immunocytochemical studies using antibodies directed against neurotransmitter substances and the enzymes involved in their biosynthesis.

Synaptic transmission (Fig. 1.6) is essentially a sequence of three different processes:

The excitatory impulse (action potential) arriving at the axon terminal depolarizes the presynaptic membrane, causing voltage-dependent calcium channels to open. As a result, calcium ions flow into the terminal bouton and then interact with various proteins to cause fusion of synaptic vesicles with the presynaptic membrane. The neurotransmitter molecules within the vesicles are thereby released into the synaptic cleft.

The neurotransmitter molecules diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane.

The binding of neurotransmitter molecules to receptors causes ion channels to open, inducing ionic currents that cause either a depolarization or a hyperpolarization of the postsynaptic membrane—i.e., either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP).

Thus, synaptic transmission results in either an excitation or an inhibition of the postsynaptic neuron.

In addition to these fast-acting transmitter-gated or ligand-gated ion channels, there are also G-protein-coupled receptors that generate a much slower response by means of an intracellular signal cascade.

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Neurons and Synapses · 9	1

Mg2+

Ca2+

Glutamate

Fig. 1.6 Synaptic transmission at a glutamatergic (excitatory) synapse (schematic drawing). The arriving action potential induces an influx of Ca2+ (1), which, in turn, causes the synaptic vesicles (2) to fuse with the presynaptic membrane, resulting in the release of neurotransmitter (in this case, glutamate) into the synaptic cleft (3). The neurotransmitter molecules then diffuse across the cleft to the specific receptors in the postsynaptic membrane (4) and bind to them, causing ion channels (5) to open, in this case Na+ channels. The resulting Na+ influx, accompanied by a Ca2+ influx, causes an excitatory depolarization of the postsynaptic neuron (excitatory postsynaptic potential, EPSP). This depolarization also removes a blockade of the so-called NMDA receptor by Mg2+ ions. From: Kahle W and Frotscher M: Taschenatlas der Anatomie, vol. 3, 8th ed., Thieme, Stuttgart, 2002.

Chemical and electrical synapses. The type of synaptic transmission described above, involving the release and receptor binding of a neurotransmitter, is the type most commonly found. There are also so-called electrical synapses in which the excitation is transmitted directly to the next neuron across a gap junction.

Types of synapses. Synapses mediate the transfer of information from one neuron to the next; the synapses that bring information to a particular cell are known as its input synapses. Most input synapses are to be found on a cell’s dendrites (axodendritic synapses). The dendrites of many neurons (e. g., cortical pyramidal cells) possess thornlike processes, the dendritic spines, that enable the compartmentalization of synaptic input. Many spines contain a spine apparatus for the internal storage of calcium ions. The synapses on dendritic spines are mainly asymmetrical, excitatory synapses.

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110 · 1 Elements of the Nervous System

Input synapses are found not only on the dendrites but also on the cell body itself (perikaryon; axosomatic synapses) and even on the axon and its initial segment, the axon hillock (axo-axonal synapses).

Convergence and divergence of synaptic connections. In general, each individual neuron receives information through synapses from many different neurons and neuron types (convergence of information transfer). The neuron can, in turn, make synaptic contact with a large number of other neurons through numerous collateral axonal branches (divergence of information transfer).

Excitation and inhibition. The nervous system is constructed in such a way that each neuron can be in one of two basic states at any moment: either the neuron is electrically discharging and transmitting information via synapses to other neurons, or else it is silent. Excitatory input to the neuron causes it to discharge, while inhibitory input causes it to be silent.

It follows that neurons can be classified as excitatory and inhibitory in terms of their effect on the neurons to which they provide input. Excitatory neurons are usually principal neurons (e. g., the pyramidal cells of the cerebral cortex), which often project over long distances and thus have long axons. Inhibitory neurons, on the other hand, are often interneurons and have short axons.

Principles of neuronal inhibition (Fig. 1.7). Collaterals of excitatory cells can activate inhibitory interneurons, which then inhibit the principal neuron itself (recurrent inhibition, a form of negative feedback). In forward inhibition, collaterals of principal neurons activate inhibitory interneurons that then inhibit other principal neurons. When an inhibitory neuron inhibits another inhibitory neuron, the resulting decrease in inhibition of the postsynaptic principal cell causes a net increase in its activity (disinhibition).

Neurotransmitters and Receptors

Excitatory and inhibitory neurotransmitters. In classic neuroanatomical studies, neurons were divided into two major types on the basis of their shape and the length of their projections: principal neurons with distant projections were called Golgi type I neurons, while interneurons with short axons were called Golgi type II neurons. Currently, neurons are usually classified according to their neurotransmitter phenotype, which generally determines whether they

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Neurotransmitters and Receptors · 11	1

Fig. 1.7 Three types of neuronal inhibition. a, Recurrent inhibition. b, Forward inhibition. c, Disinhibition. From: Kahle W and Frotscher M: Taschenatlas der Anatomie, vol. 3, 8th ed., Thieme, Stuttgart, 2002.

are excitatory or inhibitory. The commonest excitatory neurotransmitter in the CNS is glutamate, while the commonest inhibitory neurotransmitter is γ- aminobutyric acid (GABA). The inhibitory neurotransmitter in the spinal cord is glycine. Acetylcholine and norepinephrine are the most important neurotransmitters in the autonomic nervous system but are also found in the CNS. Other important neurotransmitters include dopamine, serotonin, and various neuropeptides, many of which have been (and continue to be) identified; these are found mainly in interneurons.

Ligand-gated receptors. Ligand-gated ion channels are constructed of multiple subunits that span the cell membrane. The binding of neurotransmitter to the receptor opens the ion channel (i.e., makes it permeable) for one or more particular species of ion.

Excitatory amino acid receptors. Glutamate receptors are subdivided into three types called AMPA, NMDA, and kainate receptors. Glutamate binding to an AMPA receptor results in an influx of Na+ ions, which depolarizes the cell. The activation of an NMDA receptor also causes an Na+ influx, accompanied by a Ca2+ influx. The NMDA receptor, however, can be activated only after the

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