A synapse is the gap that is present between two neurons. Synaptic transmission (also known as neurotransmission) is the process by which action potentials are communicated between neurons in the nervous system across this space.
Successful transmission relies on the neurotransmitter being readily available, the release of the neurotransmitter via exocytosis, successful binding at post-synaptic receptors, a response by the post-synaptic cell and removal or deactivation of the neurotransmitter.
This article shall discuss the various stages of synaptic transmission as well as relevant clinical conditions.
Synthesis and Storage of Neurotransmitters
The first step required for synaptic transmission is the synthesis and storage of various neurotransmitters. Some neurotransmitters, for example Acetylecholine (ACh) are synthesised within the axon. Precursors for these can either be taken up by receptors on the membrane of the synaptic terminal or may be byproducts of other processes within the cell. Enzymes required for neurotransmitter synthesis are generally produced in the cell body of the neuron and transported along the axon to the terminal. ACh for example, is made up of choline and acetate and its synthesis requires the enzyme choline acetyltransferase.
Other neurotransmitters, for example the neuropeptides (larger neurotransmitters, including endogenous opioids), are made within the cell body of the neuron as their production requires the formation of peptide bonds. Neuropeptide synthesis occurs broadly in the same way as any secretory protein – via translation and processing in the endoplasmic reticulum. Following this they are transported to the synaptic terminal, rather than out of the cell via exocytosis.
Once they have been produced, neurotransmitters are generally stored in vesicles within the synaptic terminal until an action potential arrives, resulting in their release.
Further information on neurotransmitters and specific examples can be found here.
When an action potential arrives at the synaptic terminal it stimulates neurotransmitter release. The arrival of the action potential leads to the opening of voltage gated calcium channels, resulting in an influx of calcium ions into the synaptic terminal.
These calcium ions lead to the migration of neurotransmitter containing vesicles to the pre-synpatic membrane, where the neurotransmitters are then released into the synaptic cleft.
Neurotransmitters then diffuse across the synaptic cleft to the post-synaptic membrane, where they bind to various receptors. There are two types of post-synaptic receptors a neurotransmitter can bind to:
- Ionotropic receptors – these are also known as ligand-gated ion channels and act to rapidly depolarise the post-synaptic neuron and continue the action potential (or hyperpolarise it and inhibit action potential generation)
- Metabotropic receptors – G protein coupled receptors that result in a slower and generally more prolonged response in the post-synaptic neuron via secondary messengers
Further information on the generation of action potentials can be found here.
Inactivation/Removal of Neurotransmitters
Following the generation (or inhibition) of an action potential at the post-synaptic membrane the neurotransmitter remaining in the synaptic cleft needs to either be inactivated or removed. There are various processes that take place depending on the neurotransmitter:
- Re-uptake by pre-synaptic neuron – some neurotransmitters, for example serotonin, are removed from the synaptic cleft by transporter proteins and carried back into the pre-synaptic neuron. They are then either re-packaged into vesicles for future transmission or broken down by enzymes in the neuron.
- Breakdown within the synaptic cleft – ACh, for example, has a specific enzyme, acetylcholinesterase, present within the synaptic cleft that is responsible for inactivating it. This enzyme is present in all cholinergic synapses and breaks ACh down into its component parts via hydrolysis
- Diffusion into surrounding areas
Summary of Synaptic Transmission
Synaptic transmission, therefore, can be summarised as the following steps:
- Synthesis of neurotransmitter
- Storage of neurotransmitter in vesicles
- Release of neurotransmitter into synaptic cleft
- Binding of neurotransmitter to post-synaptic receptors
- Removal/deactivation of neurotransmitter
Clinical Relevance – Acetylcholinesterase Inhibitors
Acetylcholinesterase inhibitors are a class of drug that inhibit the activity of acetylcholinesterase within the synaptic cleft. This has the knock on effect of increasing cholinergic transmission, as there is more ACh present within the synaptic cleft and it remains there for a longer period of time.
Examples of this drug class include pyridostigmine, rivastigmine and donepezil.
They can be used to treat a variety of diseases:
- Myasthenia Gravis – although in this disease they increase cholinergic activity at the neuromuscular junction rather than in synaptic transmission
- Alzheimer’s disease
- To reverse the effect of non-depolarising muscle relaxants, such as suxamethonium
As cholinergic neurotransmission is widespread throughout the body they can have many side effects, such as bradycardia; hypotension; diarrhoea; excessive salivation and muscle spasm.