Neurotransmitter Function

BASIC CIRCUITRY

In a classical neural pathway, such as that depicted in Fig. 1.3, neuron A must excite neuron B and at the same time inhibit neuron C in order to optimise the excitation of B. It could achieve this with one NT able to activate receptors linked to different events on B and C. Of course, neuron C would have other inputs, some of which would be excitatory and if the same NT was used it could activate the inhibitory mechanism on C as well. Also, the NT released from A might be able to stimulate as well as inhibit neuron C (Fig. 1.3(a)). Even the provision of separate receptors linked to excitation and inhibition would not overcome these problems since both would be accessible to the NT. One possible solution, used in the CNS, is to restrict the NT to the synapse at which it is released by structural barriers or rapid degradation. Also the inputs and receptors linked to excitation could be separated anatomically from those linked to inhibition and, in fact, there is electrophysiological and morphological evidence that excitatory synapses are mainly on dendrites and inhibitory ones on the soma of large neurons (Fig. 1.3(b)). Nevertheless, the problem of overlap would be eased if two NTs were released, one to activate only those receptors linked to excitation and another to evoke just inhibition, i.e. place the determinant of function partly back on the NT (Fig. 1.3(c)). This raises a different problem which has received much consideration. Can a neuron release more than one NT?

It was generally assumed that it cannot and this became known as Dale's Law. During his studies on antidromic vasodilation he wrote (1935) 'When we are dealing with two different endings of the same sensory neuron, the one peripheral and concerned with vasodilation and the other at a central synapse, can we suppose that the discovery and identification of a chemical transmitter at axon reflex dilation would furnish a hint as to the nature of the transmission process at a central synapse. The possibility has at least some value as a stimulus to further experiments'.

This it certainly has been and in the last few years much evidence has been presented to show that more than one substance (but not necessarily more than one conventional NT) can co-exist in one nerve terminal. This does not disprove Dale's Law (so called), since he was referring to 'a' not 'the' NT and to different endings of one neuron. In fact he was simply saying that if a neuron uses a particular transmitter at one of its terminals it will use it at another, although he did not add, irrespective of whether or not it uses more than one NT. This makes good sense especially since it is difficult to conceive how a neuron could achieve, let alone control, the release of different NTs from different terminals, unless the NTs were synthesised solely at the terminals independently of the cell body. In that way different substances might be released from different terminals of a neuron by arriving action potentials without the neuron having to do anything special

Figure 1.3 Some possible basic neurotransmitter-synaptic arrangements for the excitation and inhibition of different neurons. (a) The single NT activates neuron B and inhibits neuron C by being able to activate both excitatory and inhibitory receptors or, more probably, acting on one receptor linked to both events. There is potential, however, for the NT to activate any inhibitory receptors that may be on B or excitatory receptors on C. (b) The same NT is used as in (a) but the excitatory receptors are now only on dendrites and separated from the inhibitory receptors only on the soma. There is less chance of unwanted mixed effects. (c) Neuron A releases distinct excitatory and inhibitory NTs from its two terminals each acting on specific and morphologically separated receptors. But this depends on a neuron being able to release two NTs. (d) Neuron A releases the same NT from both terminals. It directly excites B but inhibits C through activating an inhibitory interneuron (I) which releases an inhibitory NT onto specific receptors on C. This last scheme (d) is clearly more functional and is widely used

Figure 1.3 Some possible basic neurotransmitter-synaptic arrangements for the excitation and inhibition of different neurons. (a) The single NT activates neuron B and inhibits neuron C by being able to activate both excitatory and inhibitory receptors or, more probably, acting on one receptor linked to both events. There is potential, however, for the NT to activate any inhibitory receptors that may be on B or excitatory receptors on C. (b) The same NT is used as in (a) but the excitatory receptors are now only on dendrites and separated from the inhibitory receptors only on the soma. There is less chance of unwanted mixed effects. (c) Neuron A releases distinct excitatory and inhibitory NTs from its two terminals each acting on specific and morphologically separated receptors. But this depends on a neuron being able to release two NTs. (d) Neuron A releases the same NT from both terminals. It directly excites B but inhibits C through activating an inhibitory interneuron (I) which releases an inhibitory NT onto specific receptors on C. This last scheme (d) is clearly more functional and is widely used to achieve it. Thus neuron A (Fig. 1.3) could then conceivably always release one NT at B and another at C or even two NTs at both but probably could not vary their release independently at different (or the same) synapses.

Fortunately there is another way in which one neuron can excite and inhibit different neurons using just one NT. Neuron A could excite B and inhibit C by the introduction of an inhibitory interneuron the activation of which by A, using the same excitatory NT as at B, automatically inhibits C (Fig. 1.3(d)). This form of inhibition is quite common in the CNS and in fact much inhibition is mediated by these so-called short-axon interneurons and a neuron may inhibit itself through feedback via an axon collateral synapsing onto an adjacent inhibitory short-axon interneuron (Fig. 1.2).

It might therefore be possible to set up a CNS with two NTs exerting fast excitatory and inhibitory effects through different receptors, situated on different parts of the neuron provided those were the only effects wanted. But this is not so. One neuron can receive hundreds of inputs and its activity and responsiveness is in fact balanced by such inputs producing different effects at differing speeds by using different NTs. So what are these different effects and how are they produced?

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