A synapse is a gap that is present between two neurons. Action potentials are communicated across this synapse by synaptic transmission (also known as neurotransmission).
Neurotransmission requires the release of a readily available neurotransmitter by exocytosis, binding at post-synaptic receptors, an appropriate response by the post-synaptic cell and removal or deactivation of the neurotransmitter.
In this article we shall look at the stages of synaptic transmission and clinical conditions that arise in its pathology.
Synthesis and Storage of Neurotransmitters
This is the first step of synaptic transmission. Some neurotransmitters (eg acetylcholine, ACh) are synthesised in the axon while others (eg neuropeptides) are made in the cell body.
- Acetylcholine– synthesised within the axon. Precursors (choline, acetate) taken into the cell by membrane channels or created as byproducts of other processes. Precursors used to synthesise neurotransmitters via enzymes (choline acetyltransferase) transported from the cell body where it is made to the axon terminal.
- Endogenous opioids – a neuropeptide (larger neurotransmitter) made within the cell body to allow formation of peptide bonds. Made as any secretory protein via transcription in the nucleus and translation in the endoplasmic reticulum before being transported to the synaptic terminal ready for exocytosis.
Once synthesised, neurotransmitters are stored in vesicles within the synaptic terminal until an action potential arrives, causing their release.
Action potentials arriving at the synaptic terminal leads to the opening of voltage gated calcium channels. This allows an influx of calcium in the terminal resulting in the migration of neurotransmitter storage vesicles to the pre-synaptic membrane. These vesicles fuse with the cell membrane (exocytosis) under the influence of calcium causing neurotransmitter release into the synaptic cleft.
Neurotransmitter in the synaptic cleft diffuses across the gap to the post-synaptic membrane. Here, they can bind to two types of post-synaptic receptors.
|Name||Inotropic receptors||Metabotropic receptors|
|Type||Ligand gated ion channels||G protein coupled receptors|
|Response||Channel allows ion flux to change cell voltage||Receptor acts through secondary messengers to cause cellular effects|
|Speed of response||Rapid||Slow|
|Length of response||Short-acting||Prolonged response|
This can cause either depolarisation to promote or hyperpolarisation to inhibit action potential generation in the post-synaptic neurone.
Inactivation/Removal of Neurotransmitters
Once the post-synaptic membrane has responded the neurotransmitter in the synaptic cleft is either inactivated or removed. This can be done in several ways:
- Re-uptake – serotonin is taken back into the pre-synaptic neurone by transporter proteins in its membrane. These neurotransmitters are then either recycled by re-packaging into vesicles or broken down by enzymes
- Breakdown – acetylcholine is broken down by acetylcholinesterase present in the synaptic cleft, inactivating the neurotransmitter
- Diffusion into surrounding areas
Clinical Relevance – Acetylcholinesterase Inhibitors
Acetylcholinesterase inhibitors are a class of drug that inhibit the activity of acetylcholinesterase within the synaptic cleft. This increases cholinergic transmission as ACh is present within the synaptic cleft for a longer period of time.
These drugs, such as pyridostigmine, rivastigmine and donepezil, can be used to treat various conditions:
- Myasthenia gravis – the inhibition of acetylcholinesterase works at the neuromuscular junction rather than at the synaptic cleft in this disease
- Alzheimer’s disease
- To reverse the effect of non-depolarising muscle relaxants, such as suxamethonium
As cholinergic transmission is widespread throughout the body these drugs can cause many side effects such as bradycardia, hypotension, diarrhoea, excessive salivation, muscle spasm.