Nerve Conduction And Synaptic Integration
Action potential propagation is achieved by local current spread and is made possible by the large safety factor in the generation of an action potential as a consequence of the positive feedback of Na+ channel activation in the rising phase of the nerve impulse (see Chapter 15). However, the use of local current spread does set constraints, not only on the velocity of nerve conduction; it also influences the fidelity of the signal being conducted. The nervous system overcomes these difficulties by insulating nerve fibres above a given diameter with myelin, which is periodically interrupted by the nodes of Ranvier.
• In unmyelinated axons an action potential at one site leads to depolarization of the membrane immediately in front and theoretically behind it, although the membrane at this site is in its refractory state and so the action potential is only conducted in one direction (see Chapter 15). The current preferentially passes across the membrane (because of the high internal resistance of the axoplasm) and is greatest at the site closest to the action potential. However, while nerve impulse conduction is feasible and accurate in unmyelinated axons, especially in the very small diameter fibres where the internal axoplasmic resistance is very high, it is nevertheless slow. Conduction velocity can therefore be increased by either increasing the axon diameter (of which the best example is the squid giant axon with a diameter of ∼1 mm) or insulating the axon using a high-resistance substance such as the lipid-rich myelin.
• Conduction in myelinated fibres follows exactly the same sequence of events as in unmyelinated fibres, but with a crucial difference: the advancing action potential encounters a high-resistance low-capacitance structure in the form of a nerve fibre wrapped in myelin. The depolarizing current therefore passes along the axoplasm until it reaches a low-resistance node of Ranvier with its high density of Na+ channels and an action potential is generated at this site. The action potential therefore appears to be conducted down the fibre, from node to node – a process termed saltatory conduction. The advantage of myelination is that it allows for rapid conduction while minimizing the metabolic demands on the cell. It also increases the packing capacity of the nervous system, so that many fast-conducting fibres can be accommodated in smaller nerves. As a result most axons over a certain diameter (∼1 μm) are myelinated.
Disturbances in nerve conduction are clinically seen when there is a disruption of the myelin sheath, e.g. in the peripheral nervous system (PNS) in inflammatory demyelinating neuropathies such as the Guillain–Barré syndrome and in the central nervous system (CNS) with multiple sclerosis (see Chapter 62). In both conditions there is a loss of the myelin sheath, especially in the area adjacent to the node of Ranvier, which exposes other ion channels, as well as reducing the length of insulation along the axon. The result is that the propagated action potential has to depolarize a greater area of axolemma, part of which is not as excitable as the normal node of Ranvier because it contains fewer Na+ channels. This leads to slowing of the action potential propagation and, if the demyelination is severe enough, actually leads to an attenuation of the propagated action potential to the point that it can no longer be conducted – so-called conduction block.
Each central neurone receives many hundreds of synapses and each input is integrated into a response by that neurone, a process that involves the summation of inputs from many different sites at any one time (spatial summation) as well as the summation of one or several inputs over time (temporal summation).
The presynaptic nerve terminal usually contains one neurotransmitter, although the release of two or more transmitters at a single presynaptic terminal has been described – a process termed cotransmission (see Chapter 18). The amount of neurotransmitter released is dependent not only on the degree to which the presynaptic terminal is depolarized, but also the rate of neurotransmitter synthesis, the presence of inhibitory presynaptic autoreceptors and presynaptic inputs from other neurones in the form of axoaxonic synapses (see Chapter 18). These synapses are usually inhibitory (presynaptic inhibition) and are more common in sensory path- ways (see, for example, Chapter 32).
The released neurotransmitter acts on a specific protein or receptor in the postsynaptic membrane and in certain synapses on presynaptic autoreceptors (see Chapter 18). When this binding leads to an opening of ion channels with a cation influx in the postsynaptic process with depolarization, the synapse is said to be excitatory, while those ion channels that allow postsynaptic anion influx or cation efflux with hyperpolarization are termed inhibitory.
• Excitatory postsynaptic potentials (EPSPs) are the depolarizations recorded in the postsynaptic cell to a given excitatory synaptic input. The depolarizations associated with the EPSPs can go on to induce action potentials if they are summated in either time or space. Spatial summation involves the integration by the postsynaptic cell of several EPSPs at different synapses with the summed depolarization being sufficient to induce an action potential. Temporal summation, in contrast, involves the summation of inputs in time such that each successive EPSP depolarizes the membrane still further until the threshold for action potential generation is reached.
• Inhibitory postsynaptic potentials (IPSPs) are hyperpolarizations of the postsynaptic membrane, usually as a result of an influx of Cl− and an efflux of K+ through their respective ion channels. IPSPs are very important in modulating the neurone’s response to excitatory synaptic inputs (see figure). Therefore inhibitory syn- apses tend to be found in strategically important sites on the neurone – the proximal dendrite and soma – so that they can have profound effects on the input from large parts of the dendritic tree. In addition, some neurones can inhibit their own output by the use of axon collaterals and a local inhibitory interneurone (feed-back inhibition), e.g. motor neurones and Renshaw cells of the spinal cord (see Chapter 37).
More long-term modulations of synaptic transmission are discussed in Chapters 40, 45 and 49, and in some disorders of the nervous system (e.g. epilepsy, multiple sclerosis) abnormal transmission of information may occur via non-synaptic mechanisms.