Hierarchical Brain

Neurotransmitter

A chemical synapse passes a signal from the presynaptic neuron to the postsynaptic neuron by releasing neurotransmitter chemicals into the gap between the two that are then detected by the postsynaptic neuron. This page gives details of this process, and includes copious Wikipedia links and some references that can provide even more detail.

An understanding of the content of this page is not required for an understanding of the hierarchy of levels of description of the workings of the human brain that are described on these web pages.

Many of the same neurotransmitter chemicals are also used in the process of neuromodulation that affects neurons and synapses over a wider area.

Overview

• A neurotransmitter is any one of various types of chemical molecules that are used at synapses to communicate between neurons, and also between glial cells and neurons.
  • Hundreds of different neurotransmitters have been identified as being used in the brain (see list of neurotransmitters), but there are just seven or eight common ones that are used at the vast majority of synapses.
  • Each of these common neurotransmitter chemicals tends to be used in specific areas in the brain, or by specific types of neurons that carry out specific functions. The chemicals, together with the effects they have in the brain, are known as neurotransmitter systems. The use of these systems is more relevant to neuromodulation than on this page.
  • A neurotransmitter generated at a synapse by the presynaptic neuron has to match up with receptors in the synapse on the postsynaptic neuron for the signal to be passed on. It can be thought of as a lock-and-key mechanism - the key has to match the lock⁹.
  • Some neurotransmitters, and therefore some synapses, have a positive influence on whether the neuron fires or not, others have a negative influence. A signal that is passed across a synapse that has a positive influence in the second neuron is called an excitatory postsynaptic potential; a signal that is passed across a synapse that has a negative influence in the second neuron is called an inhibitory postsynaptic potential.
  • The workings of this chemical interface in the synapse junction can also be affected by the chemical environment external to the neurons. This is called neuromodulation and the chemicals involved are then referred to as neuromodulators.

Creation/Synthesis

• Nearly all neurotransmitters are created or synthesised within the presynaptic neuron using raw materials that are found in the cytoplasm, the inside of the neuron.
  • Neurotransmitters can be divided into two categories that are created and stored in different ways: small molecules such as monoamines, and neuropeptides that are short strings of amino acids.
    • Small molecule neurotransmitters are created and stored within the presynaptic neuron’s axon terminal (sometimes called the synaptic bouton), which means they can be released very quickly when required.
    • All small molecule neurotransmitters (except one called noradrenaline, also called norepinephrine) are created or synthesised by enzymes that are located in the cytoplasm, and therefore are available at the axon terminal¹.
    • Neuropeptides are synthesised in the presynaptic neuron’s cell body or soma and must be transported to the terminal, which means they are slower to be released than small molecule neurotransmitters.
  • It used to be thought that a single neuron produced just one neurotransmitter at all its synapses (known as Dale’s principle), but it is now known that this is not the case.
    • Many neurons produce more than one neurotransmitter, known as cotransmission, and cases have been found where different neurotransmitters have different effects at different synapses (see Dana Foundation article on neurotransmitters).
    • It is now known that, typically, a neuron will synthesise and release only one type of small molecule neurotransmitter, but can also synthesise and release more than one neuropeptide².
    • Neurons are often classified by the main neurotransmitter that they produce, even though they may produce others in lesser volumes.

Storage

• After they have been created, and until they are required to be released, nearly all neurotransmitters are contained in structures within the cell called vesicles, which are moved to the site of the synapse if necessary.
  • All cells, including neurons, have multiple sub-units inside the cell, known as organelles.
    • There are many different types of organelles found in nearly all living cells. Obvious examples include the nucleus and mitochondria.
    • A vesicle is an example of an organelle, and it is used in normal cells for a number of functions. The ones that transport neurotransmitters to synapses are called synaptic vesicles.
  • A vesicle is a tiny spherical bubble with a membrane similar to that of any cell, but thinner. The membrane also contains two types of proteins, one type to enable the vesicle to collect the neurotransmitter, and another to allow it to expel it:
    1. Vesicular transport proteins that consist of proton pumps to generate the energy that power various transporter proteins that move neurotransmitter molecules into the vesicle from the neuron cytoplasm.
    2. So-called SNARE proteins that allow the vesicle to dock with, and eventually ejects its contents outside of, the neuron membrane (more on this below).
  • Vesicles containing neuropeptides that are created in body of the neuron are moved to the site of the synapse by an amazing process called anterograde transport.
    • There are fast and slow versions of anterograde transport, and synaptic vesicles use the fast method³.
  • Small molecule gases that are neurotransmitters, such as nitric oxide and carbon monoxide, now usually known as gasotransmitters, are not stored in vesicles but are released from a synapse when an action potential occurs.

Release

• When an action potential is raised in the presynaptic neuron, the neurotransmitter chemicals are released into the gap between the two neurons at the synapse.
  • The complex process by which an action potential causes the release of neurotransmitters from synaptic vesicles starts with the movement of ions, in this case positive calcium ions.
  • This causes the vesicles that are already docked to the membrane in the active zone of the synapse to have proteins on their surfaces activated. This process is called vesicle fusion and is enabled by a structure in the neuron membrane called a porosome.
  • Only vesicles that are within the so-called active zone of the presynaptic membrane are affected. Others away from this zone are held in reserve⁴.
  • The process by which cells can expel the contents of a vesicle from the inside to the outside is called exocytosis.
  • This process is used in all cells to get rid of waste products, but also to transfer DNA, proteins, secrete hormones, and release neurotransmitters.
  • It is a mind-boggling thought that neuron-to-neuron communication, and therefore all the functioning of my brain, may have evolved from processes that were originally used to secrete hormones or dispose of waste from a cell¹³.
  • Docking of a vesicle to the presynaptic neuron membrane at the so-called active zone in the synapse happens through the interaction of three membrane-bound proteins that are collectively called SNARE proteins⁵.
    • The first is synaptobrevin which is on the membrane of the synaptic vesicle.
    • The other two, called syntaxin and SNAP-25 are both on the membrane of the presynaptic neuron at the synapse active zone.
    • Two of these proteins, synaptobrevin and SNAP-25, have their function degraded by neurotoxin poisons that are produced by bacteria commonly found in soil:
      • Synaptobrevin is affected by tetanospasmin that is produced by clostridium tetani and causes tetanus.
      • SNAP-25 is affected by botulinum toxin that is produced by clostridium botulinum and causes botulism.
      In both cases the lack of the protein function means that vesicles cannot properly dock with the presynaptic neuron membrane, so the neurotransmitter is not released. This means that important signals in the brain are no longer passed on, resulting in partial paralysis, or other lack of brain function.
  • The activation of the synaptotagmins in the membrane of the vesicle causes them to change their shape, and this causes the vesicle to fuse with the neuron membrane and so release its contents into the synaptic space outside the cell between the two neurons, called the synaptic gap or synaptic cleft. Synaptotagmin is a calcium sensor, and when calcium is present at the active zone, synaptotagmin interacts with the SNARE proteins⁶.
  • A synaptic vesicle docks with the presynaptic neuron membrane at the synapse, becomes part of the membrane, and then the membrane opens up on the outside to allow the neurotransmitter contents of the vesicle to be released into the synaptic cleft.

Reception

• The neurotransmitters in the synaptic cleft bind onto receptors on the postsynaptic neuron, and trigger a postsynaptic current.
  • These receptors only open in response to one specific neurotransmitter, and no other, it is like a lock-and-key mechanism⁹.
  • Whether there is a positive or negative influence on the postsynaptic neuron is actually determined by the exact type of ion channel that is activated by the neurotransmitter, but in most cases a single neurotransmitter has the same effect at most synapses, so it is generally true to say that a particular neurotransmitter has either an excitatory or an inhibitory effect¹⁴.
  • Receptors fall into two main categories: ligand-gated channels and G-protein coupled receptors⁷.
  • Ligand-gated channels, also called ionotropic receptors, or neurotransmitter-gated channels, are ion channels that open in response to the binding of a neurotransmitter⁸.
    • These receptors act open ion channels immediately in response to the detection of the neurotransmitter.
    • They normally create short-term postsynaptic potentials of just a few milliseconds.
    • However, recent evidence suggests that these potentials can be propagated in dendrites due to a type of mini-action protential¹⁵.
    • Excitatory ionotropic receptors allow positive sodium ions to cross the postsynaptic membrane into the postsynaptic neuron, whereas inhibitory ionotropic receptors allow negative chloride ions in¹⁰.
  • G protein-coupled receptor (GPCRs), also called metabotropic receptors, are membrane-bound proteins that activate G-proteins in response to the binding of a neurotransmitter.
    • These receptors open ion channels only indirectly as a result of other interim proteins being produced, often called second messengers.
    • These are slower to react than ionotropic receptors, but they can have long-lasting effects ranging from seconds to days¹¹.
    • The longer term changes are caused by the effect of some second messengers on transcription factors that control mRNA synthesis and therefore can change gene expression¹⁶.
    • Some second messenger molecules can cross the postsynaptic neuron membrane and influence other synapses, so becoming a neuromodulator.

Recycling

• The neurotransmitter molecules in the synaptic cleft are recycled by three different mechanisms: by being transported back into the presynaptic neuron, by being broken down in the synaptic cleft or by being transported into glial cells where they are broken down¹².
  1. Some neurotransmitters are taken back into the presynaptic neuron by one of the many types of neurotransmitter transporters that are a specific type of membrane transport protein that span the presynaptic neuron membrane.
  2. Other neurotransmitters are broken down by enzymes in the synaptic cleft, and then the component molecules are taken back into the presynaptic neuron by the similar transporter proteins.
  3. Some neurotransmitters are taken in to glial cells by neurotransmitter transporters where they are broken down, and then the components are transported out of the glial cells into the synaptic cleft and then back into the presynaptic neuron.
• The vesicles themselves are recycled after releasing their contents by two different mechanisms by being merged into the presynaptic neuron membrane or by closing up again. Which of these takes place may depend on the level of available calcium ions, or perhaps on other variables - this area, as well as others relating to the recycling of vesicles, is not yet fully understood¹⁷.
  1. Full collapse fusion is the usual name for when the vesicle fully merges with the presynaptic neuron membrane, so that all the contents of the vesicle are then outside the neuron. The membrane of the vesicle becomes part of the neuron membrane. At a later time, a new vesicle can be created from this part of the neuron membrane.
  2. Kiss-and-run fusion is the unusual name for when the vesicle merges with the presynaptic neuron, but not fully, so that perhaps not all the neurotransmitter inside the vesicle is released. Then the hole closes up again, so the vesicle still exists, possibly with some neurotransmitter remaining inside.

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References For information on references, see structure of this website - references

1. ^ Foundations of Neuroscience - Open Edition - Henley (2021) downloadable here, Chapter 9 entitled “Neurotransmitter synthesis and storage”
   Under the heading “Synthesis and Storage of Small Molecule Transmitters” (page 93 in downloaded version): “Most small molecule neurotransmitters are synthesized by enzymes that are located in the cytoplasm (the exception is norepinephrine...). This means that small molecule neurotransmitters can be synthesized and packaged for storage in the presynaptic terminal using enzymes present in the terminal.”
2. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 9
   End of chapter introduction (page 92 in downloaded version): “Additionally, a neuron typically will synthesize and release only one type of small molecule neurotransmitter but can synthesize and release more than one neuropeptide.”
3. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 9
   Under the heading “Synthesis and Storage of Neuropeptides” (pages 102-103 in downloaded version): “Unlike small molecule neurotransmitters, neuropeptides are synthesized in the cell body and transported to the axon terminal.
   Under the heading “Axonal Transport”: “The packaged peptides need to be transported to the presynaptic terminals to be released into the synaptic cleft. ... The packaged neuropeptides are transported to the synaptic terminals via fast anterograde axonal transport mechanisms.”
4. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 10 entitled “Neurotransmitter release”
   Under the heading “Active zones” (pages 107 in downloaded version): “The voltage-gated calcium channels are concentrated in the presynaptic terminal at active zones, the regions of the membrane where small molecule neurotransmitters are released. At active zones, some synaptic vesicles are docked and are ready for immediate release upon arrival of the action potential. Other neurotransmitter-filled vesicles remain in a reserve pool outside of the active zone.”
5. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 10
   Under the heading “Vesicle Docking” (page 108 in downloaded version): “Docking of synaptic vesicles packaged with small molecule neurotransmitters occurs through the interaction of three membrane-bound proteins called SNARE proteins. Synaptobrevin is called a v-SNARE because it is located on the Vesicular membrane. Syntaxin and SNAP-25 are called t-SNARES because they are located on the terminal membrane, which is the Target membrane. The interaction of these three proteins leads to vesicle docking at the active zone.”
6. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 10
   Under the heading “Exocytosis” (page 109 in downloaded version): “The influx of calcium through the voltage-gated calcium channels initiates the exocytosis process that leads to neurotransmitter release. Calcium enters the cell and interacts with another vesicle-bound protein called synaptotagmin. This protein is a calcium sensor, and when calcium is present at the active zone, synaptotagmin interacts with the SNARE proteins. This is the first step toward exocytosis of the synaptic vesicle.”
7. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 10
   Under the heading “Neurotransmitter Action” (page 110 in downloaded version): “After exocytosis of the transmitter molecules, they enter the synaptic cleft and bind to receptors on the postsynaptic membrane. Receptors fall into two main categories: ligand-gated channels and G-protein coupled receptors.”
8. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 11 entitled “Neurotransmitter action: ionotropic receptors”
   Start of introduction (page 113 in downloaded version): “Ionotropic receptors, also called neurotransmitter-gated or ligand-gated channels, are ion channels that open in response to the binding of a neurotransmitter.”
9. ^ ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 11
   Paragraph after animation 11.1 (page 115 in downloaded version): “The receptors can only be opened by a specific ligand. Neurotransmitters and receptors fit together like a lock and key; only certain neurotransmitters are able to bind to and open certain receptors.”
10. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 11
    At the end, under the heading “Key takeaways” (page 129 in downloaded version): “Glutamate is an excitatory neurotransmitter that opens non-selective cation channels that allow the influx of sodium, causing an EPSP. GABA and glycine are inhibitory neurotransmitters that open chloride channels, causing an IPSP.”
11. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 12 entitled “Neurotransmitter action: G-protein-coupled receptors”
    End of introduction (page 123 in downloaded version): “GPCRs [G-protein-coupled receptors] have slower effects than ionotropic receptors, but they can have long-lasting effects, unlike the brief action of a postsynaptic potential.”
12. ^ Ibid. Foundations of Neuroscience - Open Edition - Henley, Chapter 13 entitled “Neurotransmitter clearance”
    Summary at start of chapter (page 136 in downloaded version): “After neurotransmitters have been released into the synaptic cleft, they act upon postsynaptic receptors.... That action must be terminated in order for proper neuronal communication to continue. This is accomplished mainly through two processes: neurotransmitter transport and/or degradation. Transport physically removes the neurotransmitter molecule from the synaptic cleft. Degradation breaks down the neurotransmitter molecule by enzyme activity.”
13. ^ Principles of Neural Science - Fifth edition - Kandel et al. McGraw-Hill US 2012 - or see GoogleScholar.
    Page 185, top of right-hand column, under the heading “Neurotransmitters Bind to Postsynaptic Receptors”: “Indeed, chemical synaptic transmission can be seen as a modified form of hormone secretion.”
14. ^ Ibid. Principles of Neural Science
    Page 211, end of right-hand column, under the heading “Excitatory and Inhibitory Synapses Have Distinctive Ultrastructures”: “ ...the effect of a synaptic potential - whether it is excitatory or inhibitory - is determined not by the type of transmitter released from the presynaptic neuron but by the type of ion channels in the postsynaptic cell activated by the transmitter. Although some transmitters can produce both excitatory and inhibitory postsynaptic potentials, by acting on distinct classes of ionotropic receptors at different synapses, most transmitters produce a single predominant type of synaptic response; that is, a [particular] transmitter is usually inhibitory or excitatory.”
15. ^ Ibid. Principles of Neural Science
    Page 228, first paragraph under the heading “Dendrites Are Electrically Excitable Structures That Can Fire Action Potentials”: “Propagation of signals in dendrites was originally thought to be purely passive. However, intracellular recordings from the cell body of neurons in the 1950s and from dendrites beginning in the 1970s demonstrated that dendrites could produce action potentials. Indeed, we now know that the dendrites of most neurons contain voltage-gated Na⁺, K⁺, and Ca²⁺ channels in addition to ligand-gated channels and leakage channels.”
16. ^ Ibid. Principles of Neural Science
    Page 255, right-hand column, end of first paragraph under the heading “Second Messengers Can Endow Synaptic Transmission with Long-Lasting Consequences”: “Second messengers can also effect long-term changes lasting days to weeks as a result of alterations in a cell’s expression of specific genes. Such changes in gene expression result from the ability of second-messenger cascades to control the activity of transcription factors, regulatory proteins that control mRNA synthesis.”
17. ^ Synaptic vesicle recycling: steps and principles - Rizzoli 2014
    doi: 10.1002/embj.201386357 downloadable here or see GoogleScholar.
    Beginning of abstract: “Synaptic vesicle recycling is one of the best-studied cellular pathways. Many of the proteins involved are known, and their interactions are becoming increasingly clear. However, as for many other pathways, it is still difficult to understand synaptic vesicle recycling as a whole. While it is generally possible to point out how synaptic reactions take place, it is not always easy to understand what triggers or controls them.”

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