Removal of neurotransmitters from synapses

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In the last post we learned how neurotransmitters are released into a synapse upon arrival of the action potential. But after the neurotransmitters are released into the synapse, if they are allowed to stay there, it could be disastrous!!

Imagine you realize there's a mosquito on your face, and your brain sends out action potentials to configure a movement that results in you slapping your cheek to either kill or get rid of the mosquito!! Now that the mosquito is gone and your brain realizes it, it will stop sending action potentials. BUT, what if the neurotransmitters were allowed to stay wherever they were released? Recall that it is the neurotransmitter that creates an actual action not the action potential itself. The action potential is simply the messenger!!

Now, even with the mosquito gone, you're constantly slapping your own face, like a circus clown!!

Today we'll learn a few mechanisms our body has in place, so that we don't make a fool of ourselves like the above example!!!

Let's dive into it!! The neurotransmitters that were released into the synapse can not stay there!!

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image from http://agingfree.org/en-us/news/ArticleID/327/Electronic-synapses-that-can-learn-towards-an-artificial-brain

Reuptake

The first mechanism our body has is called Reuptake pumps, by which the released neurotransmitters are actively taken back or pumped back into the presynaptic terminal, where they can be either recycled into a new synaptic vesicle and be released next time an action potential comes, or it can be broken down and new neurotransmitters will be synthesized.

In an article published in the journal CNS Drugs, (link will be down in the sources)

In the last 5 years, there has been considerable progress in the molecular characterisation of multiple neurotransmitter reuptake mechanisms (or neurotransporters). Neurotransporters are high affinity reuptake proteins located in the plasma membrane of both presynaptic nerve and glial cells. They mediate the removal of the neurotransmitter from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles.

Abnormalities in these uptake mechanisms can lead to many different disease processes. But at the same time, these reuptake mechanisms are also targets for different drugs we can use to control symptoms of certain diseases. For example in a patient with depression, we can give drugs that inhibit the reuptake of neurotransmitters like serotonin, which acts to elevate mood. The article mentioned above continues to say this exact same thing,

Through an improved understanding of the modulation of the function of neurotransporters in the brain, it may be possible to identify the molecular factors underlying both the predisposition to, and the pathogenesis of, psychiatric, neurological and neurodegenerative disorders. Neurotransporters have long been regarded as primary sites of action for tri- and heterocyclic antidepressant drugs in the treatment of a variety of neuropsychiatric conditions. Nevertheless, due to their increasingly appreciated heterogeneity, as well as their specificity for distinct neuronal systems, we are currently witnessing a renaissance of various neurotransmitter reuptake mechanisms as potential targets for novel therapeutic strategies.

Inactivation

The other mechanism, our body has is to inactive the neurotransmitter in the synapses by enzymes. These enzymes are present in the synapses and metabolizes the neurotransmitters and makes them ineffective. These enzymes are also targets for certain drugs to control and treat certain diseases.

Acetylcholine (ACh) for example, is a neurotransmitter that is released at neuromuscular junction (ACh has many other functions as well at many other different places) and after it binds to it's receptor, a cascade of events take place in the muscle and makes our muscle contract. ACh is removed from the synapses by an enzyme called acetylcholinesterase.

Myasthenia gravis is a rare autoimmune condition in which antibodies produced by the immune system attack the connection between nerves and muscles (the neuromuscular junction). Nerve impulses become blocked, causing muscles to become weak and easily tired. Symptoms fluctuate in severity. Acetylcholine is a chemical messenger that carries signals between nerve and muscle. An enzyme called acetylcholinesterase breaks down acetylcholine. Some drugs that are used to treat myasthenia gravis act on acetylcholinesterase to stop the breakdown of acetylcholine. These acetylcholinesterase inhibitors increase the amount of acetylcholine available and so help muscle activation and contraction.

In myasthenia gravis, our body is producing antibodies against the ACh receptors. These antibodies are present in much higher concentration and so more of these antibodies bind to the receptors and doesn't allow enough ACh to bind, thus causing muscle weakness. But somehow if we could increase the concentration of ACh in the synapses, they would be able to knock out the antibodies and bind to more receptors. And now we have drugs like neostigmine, which is an acetylcholinesterase inhibitor and thus this drug stops the breakdown of ACh at the synapses, ensuring ACh stays in higher concentration.

In this article I just mentioned a few very common diseases, but there's still a lot more research to be done on removal of neurotransmitters and pathophysiology of a lot of psychiatric disorders and how we can target these mechanisms to formulate drugs and contribute to improving symptoms.

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