The human brain is made up of approximately 86 billion neurons which “talk” to each other using a combination of electrical and chemical (electrochemical) signals.
The places where neurons connect and communicate with each other are called synapses. Each neuron has anywhere between a few to hundreds of thousands of synaptic connections, and these connections can be with itself, neighboring neurons, or neurons in other regions of the brain. A synapse is made up of a presynaptic and postsynaptic terminal.
The presynaptic terminal is at the end of an axon and is the place where the electrical signal (the action potential) is converted into a chemical signal (neurotransmitter release). The postsynaptic terminal membrane is less than 50 nanometers away and contains specialized receptors. The neurotransmitter rapidly (in microseconds) diffuses across the synaptic cleft and binds to specific receptors.
The type of neurotransmitter released from the presynaptic terminal and the specific receptors present on the corresponding postsynaptic terminal is critical in determining the quality and intensity of information transmitted by neurons. The postsynaptic neuron integrates all the signals it receives to determine what it does next, for example, to fire an action potential of its own or not. [1][2]
Neurons
In the simplest sense, the neuron consists of a cell body, axons, and dendrites.
Cell Body
The cell body contains the nucleus and is the site of metabolic activity. Most of the neurotransmitters that will eventually be released at the synapse are synthesized here.
Dendrites
These are small projections from the cell body that serves a receptive role in the physiology of the neuron. They receive incoming signals from other neurons and relay them to the cell body, where the signals are integrated, and a response will be initiated.
Axons
Generally, the outflow tract of the neuron. It is a cylindrical tube that is covered by the axolemma and is supported by neurofilaments and microtubules. The microtubules will help to transport the neurotransmitters from the cell body down to the pre-synaptic terminal, where they will be released.
Synapses
The synapse itself is the site of transmission from the pre-synaptic neuron to the post-synaptic neuron. The structures found on either side of the synapse vary depending on the type of synapse:
Axodendritic
A connection formed between the axon of one neuron and the dendrite of another. These tend to be excitatory synapses.
Axosomatic
A direct connection between the axon of one neuron to the cell body of another neuron. These tend to be inhibitory synapses.
Axoaxonic
A connection between the terminal of one axon and another axon. These synapses generate serve a regulatory role; the afferent axon will modulate the release of neurotransmitters from the efferent axon.
The above discussion focuses on chemical synapses, which involve the release of a chemical neurotransmitter between the 2 neurons. This is the most common type of synapse in the mammalian central nervous system (CNS). However, it is important to note that there are electrical synapses, where electrical current (or signals) will pass directly from one neuron to another through gap junctions. The differences between the two will be expanded on in the mechanism section. [3][4]
Two neurons form the neurological synapse, or in some instances, a neuron and an anatomical structure. This review will focus on 2 neurons composing the synapse. Neurons initially develop from the embryonic neural tube, which has 3 layers:
The intermediate zone will go on to form the gray matter, while the nerve processes that make up the marginal zone will become white matter once myelinated.
The neurons must then differentiate from their precursors. The order in which they do this is based upon their size, with the largest neurons (motor neurons) differentiating first. Around the time of birth, the smaller neurons (sensory neurons) will develop, along with glial cells. Glial cells are cells that will aid in the differentiation of the neurons and will facilitate their growth in the direction of their target locations. Later, glial cells will participate in the reuptake of excess neurotransmitters in the synaptic cleft.
Synapses
As previously mentioned, there are 2 major types of synapses: electrical and chemical.
In mammals, the majority of synapses are chemical. Chemical synapses can be differentiated from electrical synapses by a few distinguishing criteria: they use neurotransmitters to relay the signal and vesicles are used to store and transport the neurotransmitter from the cell body to the terminal; furthermore, the pre-synaptic terminal will have a very active membrane and the post-synaptic membrane consists of a thick cell membrane made up of many receptors. In between these 2 membranes is a very distinct cleft (easily visualized with electron microscopy) and the chemical neurotransmitter released must diffuse across this cleft to elicit a response in the receptive neuron. Because of this, the synaptic delay, defined as the time it takes for current in the pre-synaptic neuron to be transmitted to the post-synaptic neuron, is approximately 0.5 to 1.0 ms.
This is different from the electrical synapse, which will typically consist of 2 membranes located much closer to each other than in a chemical synapse. These membranes possess channels formed by proteins known as connexins, which allow the direct passage of current from one neuron to the next and do not rely on neurotransmitters. The synaptic delay is significantly shorter in electrical synapses versus chemical synapses.
The rest of the discussion will focus on chemical synapses, which have a lot of variation and diversity of their own. They vary not only between shape and structure, but also the chemical that is transmitted. Synapses can be excitatory or inhibitory, and use a variety of chemical molecules and proteins that will be discussed shortly.
Multiple types of neurotransmitters used in synaptic communication including, but not limited to:
The easiest approach to understanding synaptic transmission is to think of it as a stepwise process beginning with the synthesis of the neurotransmitter and ending with its release.
Synthesis
Neurotransmitters are synthesized differently depending on which type they are. They can be a small molecule chemical, such as dopamine and serotonin, or they can be small neuropeptides, such as enkephalin.
Release
Now that the neurotransmitters are stored in the vesicles in the pre-synaptic terminal, they must be released into the cleft. Along the membrane of the vesicle and the presynaptic membrane are proteins known as SNARE proteins; these proteins are essential in the binding of the vesicles to the membrane and the release of their contents. As the action potential propagates down the pre-synaptic neuron, the membrane will depolarize. Once the action potential arrives at the pre-synaptic terminal, the depolarization of the membrane will allow the voltage-dependent calcium channels to open, allowing the rapid influx of calcium into the pre-synaptic terminal. The influx of calcium causes the SNARE proteins to activate and change conformation, allowing the fusion of vesicles to the membrane and the release of their contents. The neurotransmitter will spill into the synaptic cleft, and the vesicle membrane is recovered via endocytosis.
Receptor Activation
Once the neurotransmitter binds to the post-synaptic neuron, it can generally cause one of 2 types of receptors to be activated. It will either activate a ligand-gated ion channel or a G-protein receptor.
Signal Termination
Inactivation of the signal must involve clearing the neurotransmitter from the synapse in at least 1 of 3 ways:
It is important to note that both of the above enzymes are very frequent targets of therapeutic medications. By eliminating these enzymes, the neurotransmitter will remain in the synapse for longer, which can be beneficial in eliminating the symptoms of many disease processes.
The synapse is the fundamental functional unit of neuronal communication. Because of this, diseases that target the synapse can present with severe clinical consequences. A few examples are listed below:
Myasthenia Gravis
Myasthenia gravis is an auto-immune disease process that causes muscle weakness that usually presents in a descending fashion. It can cause ptosis, diminished facial expression, respiratory depression, and other signs/symptoms of weakness. In general, it is worse after activity and better with rest. The pathogenesis of myasthenia gravis involves diminished communication between the neuron and the muscle at the neuromuscular junction (NMJ). The reason for this is that antibodies will either block or destroy the acetylcholine receptors at the NMJ, preventing the ACh from binding and depolarizing the muscle, therefore, inhibiting contraction. These antibodies block step three (receptor activation) of the synaptic communication pathway.
Lambert-Eaton Syndrome
Lambert-Eaton syndrome is also an auto-immune condition producing dysfunction at the neuromuscular junction; however, it involves the pre-synaptic neuron. Instead of antibodies directed against the ACh receptors as in myasthenia gravis, the antibodies here are directed against the calcium channels on the pre-synaptic neuron. This prevents calcium influx from occurring, which prevents the fusion of vesicles with the pre-synaptic membrane and release of the neurotransmitters into the synapse. These antibodies prevent step two (neurotransmitter release) of the synaptic communication pathway.
Botulism/Tetanus
In both of these disease processes, the causative agent is a toxin produced by a bacteria that acts as a protease that cleaves the SNARE proteins. This prevents the release of neurotransmitters at the junction by inhibiting vesicular fusion.
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