2 Pathophysiology of Depression ^{ref 6}

2.1 Introduction - Relevance of the Pathophysiology of Depression for Clinicians

While the causes of depression are not fully understood, exciting advances in neurobiology increasingly implicate biochemical imbalances in the brain. Certain neurotransmitters are thought to control mood. Since the early 1950s, a number of theories have been proposed to explain the complex biochemical processes underlying depression. While the principal relevance of neurophysiology is still in the research arena, an understanding of neurophysiology and the biochemistry of depression is extremely useful for clinicians in understanding the biochemical treatments for depression, and in making rational decisions on pharmacological treatment.

2.2 Neurotransmission

All behavior - movement, perception, reasoning, memory, and emotion - derives from the electrochemical signals relayed from neuron to neuron in the intricate network of the brain.

How these signals are conveyed - the process of neurotransmission - must be examined closely to understand the biochemistry underlying depression.

Signals travel from neuron to neuron in complex pathways of the brain. The neurons thought to be involved in regulation of mood originate in the brainstem and project widely throughout the central nervous system in what are known as neuronal pathways.

Pathways of the brain

The neuron is the basic functional unit of the central nervous system. Each neuron contains three main parts: the dendrites, the soma or cell body, and the axon.

Each neuron receives input from many other neurons and responds by signaling many other neurons. The neuron communicates its signals by releasing chemicals called neurotransmitters.

Neurotransmission involves individual neurons receiving and sending signals. The presynaptic neuron sends the signal. The postsynaptic neuron receives the signal. This space between the neurons is the synaptic cleft. A receptor is a site on the postsynaptic neuron that receives incoming signals from neighboring neurons.

An electron micrograph of the synapse

Neurotransmission is initiated when a signal arrives in the presynaptic neuron and travels to the axon terminal. This incoming signal (which possesses an electrical charge and is also known as an action potential) triggers storage vesicles to cluster close to the neuronal membrane. These vesicles fuse with the neuronal membrane and release their contents (the neurotransmitter) into the synaptic cleft.

Neurotransmission

The neurotransmitter diffuses across the synaptic cleft toward the postsynaptic neuron. The neurotransmitter binds to specific receptor sites on the postsynaptic neuron.

What happens to the neurotransmitter when it reaches the postsynaptic neuron?

In order for the signal received by the postsynaptic neuron to be relayed to the next neuron, the receptor on the postsynaptic neuron must be connected to a protein called an effector. The effector is what carries out the response in the postsynaptic neuron.

This connection between receptor and effector is achieved by means of a coupling protein called a G protein. The G protein links the receptor to an effector, thereby allowing the neurotransmitter to produce a response. This response in the postsynaptic neuron may be either stimulatory or inhibitory. If a G protein does not couple receptor and effector, binding is not translated into chemical response, and the signal from one neuron is not relayed to the next.

Preexcitation		Excitation

After the neurotransmitter binds to the receptor sites of the postsynaptic neuron and neurotransmission is complete, residual neurotransmitter must be cleared from the synapse. One way that neurotransmitter is cleared from the synaptic cleft is by a process known as diffusion, in which a chemical substance moves from an area of high concentration to an area of lower concentration. The neurotransmitter moves out of the cleft.

Neurotransmitter can also be cleared from the synapse by a process known as reuptake.

Here, the presynaptic neuron retrieves excess neurotransmitter and "repackages" it inside storage vesicles so it can be used again. Not all excess neurotransmitter that is retrieved by the presynaptic neuron is repackaged.

These neurotransmitters are monoamines and the intracellular enzyme that breaks them down is known as monoamine oxidase or MAO. This process of breaking them down is known as degradation.

The process of neurotransmission occurs rapidly and automatically, with electrochemical signals causing neurotransmitters to be released into the synapse, receptors to be activated, and neurotransmitters to be cleared. How is this complex process regulated?

We do now know precisely how neurotransmission is regulated. Many researchers believe that there is a relationship between the amount of neurotransmitter released into the synaptic cleft and the sensitivity and/or number of receptors on the postsynaptic neuron.

The regulation of neurotransmission is believed to be a process of compensation.

Decreasing stimulation caused by a decrease in neurotransmitters can be compensated for by increasing the number of the postsynaptic receptors, a process known as up-regulation.

Up-regulation

Decreasing the amount of neurotransmitter in the synapse decreases the amount of stimulation of postsynaptic receptors. The postsynaptic neuron attempts to compensate by increasing the receptor-coupling of G proteins, and this is believed to increase the responsiveness, or sensitivity of receptors.

When stimulation is increased by an increase in the amount of neurotransmitters, the postsynaptic neuron can compensate by decreasing the number of postsynaptic receptors, a process known as down-regulation.

Down-regulation

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