Neurological Control

The Synaptic Signal

Once the action potential reaches the axonal terminal, the change in membrane potential triggers the activation of calcium channels, which allows elevation of the concentration of calcium ions in the presynaptic neuron. This rise in intracellular calcium causes synaptic vesicles to fuse with the presynaptic membrane and one or more neurotransmitters are released into the synaptic cleft. Neurotransmitters are produced and stored within a neuron and released only after neuronal depolarization, when they diffuse throughout the synaptic cleft and bind to specific receptors on the membrane of the postsynaptic neuron, or to an autoreceptor.

Often the ‘lock and key’ hypothesis is used to illustrate the interaction between a neurotransmitter and its receptor. The key (the neurotransmitter) can only unlock (activate) a lock (the receptor) if it fits perfectly into the keyhole (neurotransmitter binding site) of the lock.

Receptors and autoreceptors are sensitive to the neurotransmitter concentration in the synaptic cleft. Autoreceptors regulate the release of the neurotransmitter from the presynaptic neuron – when these presynaptic receptors are fully occupied, neurotransmitter production is stopped. Oversensitivity of autoreceptors may be implicated in the development of depression.

Almost every neurotransmitter can bind to more than one type of receptor, and each neurotransmitter can initiate different signals at the postsynaptic neuron. This all adds to the complexity of chemical signalling. Binding of a neurotransmitter to its receptor on the postsynaptic membrane can activate channels in the postsynaptic neuron resulting in a change in the membrane potential. This initiates an excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic neuron and initiates an action potential. In this way, the electrical signal or impulse is transmitted down the neuronal pathway. Once the action potential is initiated, the transmitter must then be rapidly removed from the synaptic cleft, to enable the postsynaptic cell to engage in another cycle of signal generation.

Role of Receptor Responses

Many psychiatric disorders, such as depression, are associated with either an excess or a shortage of neurotransmitters, such as serotonin, noradrenaline and glutamate. However, interest is now growing in the possible role of the altered response of receptors to neurotransmitters in psychiatric conditions.

The monoamine hypothesis of depression stated that there is a decreased concentration of monoamines in the brains of people with depression. However, it is now thought that in depression there may be an increase in the overall number of postsynaptic receptors, rather than a decrease in the number of monoamine molecules. This ‘upregulation’ of receptors would result in an increased concentration of monoamines being needed to produce a response.

The occurrence of upregulation has proved difficult to demonstrate in depressed patients, but there is evidence that antidepressant treatment reduces receptor numbers – this effect of antidepressants is sometimes known as receptor ‘downregulation’. The phenomenon is now quite well documented for selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, as well as for electroconvulsive therapy.

An alternative suggestion is that antidepressants may cause an increase in the sensitivity of postsynaptic receptors, and that reduced concentrations of neurotransmitter can produce a response that is closer to the norm. Another theory is that depression increases the sensitivity of the presynaptic autoreceptors that moderate monoamine release via a feedback mechanism. As a result, less of the neurotransmitter needs to be released before production is ‘switched off’.

Last updated: 20.12.2011