Updated: Aug 16
Neurons communicate bidirectionally, chemically and electrically, and across and outside synapses. This post provides an overview of the complexity of neuronal communication, covering Synaptic Communication, Neurotransmitter Co-Release, Terminating Neurotransmitter Action, Extra-Synaptic Transmission, Axonal Varicosities, Retrograde Transmission, Neurotransmitter Release Modulation, Autoreceptors, and Electrical Synapses.
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Neurons in the human brain primarily communicate by releasing chemical signaling molecules known as neurotransmitters (NTs). Glutamate, an amino acid, is the main excitatory NT, while γ-aminobutyric acid (GABA) is the main inhibitory NT. These molecules and others trigger responses in the postsynaptic neuron by binding to and activating specific receptors. Since most NTs can activate various receptors, there are many potential pathways for synaptic signaling. Following activation of their postsynaptic receptors, NTs are cleared from the synaptic cleft either by NT transporters or enzymes that break them down.
Neurons communicate by releasing over 200 neurotransmitters (NTs) and ions. Axon terminal buttons release neurochemicals across a 20-50-nm fluid-filled gap between presynaptic and postsynaptic structures called a synaptic cleft and into the extracellular fluid surrounding the neuron (Bear, Connors, & Paradiso, 2020). Chemical synapses produce short-duration (millisecond) and long-duration (seconds to days) changes in the nervous system. The synapse animation © 3Dme Creative Studio/Shutterstock.com.
They are functionally asymmetrical because the presynaptic neuron sends a chemical message, and the postsynaptic neuron receives it. They are structurally asymmetrical because the presynaptic element (axon) contains vesicles containing NTs, and the postsynaptic element (dendrite) doesn’t. NT release from a terminal button is called exocytosis (Breedlove & Watson, 2023). The chemical synapse graphic © rob9000/Shutterstock.com.
In the graphic below, an axon terminal button releases NTs into the synaptic cleft. NTs briefly form covalent bonds with receptors on a dendritic spine and then disengage after they initiate small graded potential changes (e.g., EPSPs or IPSPs) or more diverse, gradual, and long-lived actions (e.g., creating second messengers inside the target neuron). The axodendritic synapse graphic © nobeastsofierce/Shutterstock.com.
Synaptic transmission is a complex process that includes several key steps. First, the action potential travels down the axon and arrives at its terminal. Upon reaching the terminal, this depolarization triggers the opening of voltage-gated calcium channels in the membrane of the axon terminal, allowing Ca2+ ions to enter.
Calcium ions cause synaptic vesicles, which are filled with NT molecules, to fuse with the presynaptic membrane and rupture. This releases the NT into the synaptic cleft. The NT molecules then cross the cleft to bind to specialized receptor molecules in the postsynaptic membrane, which leads to the opening of ion channels in that membrane. This ion flow creates either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP) in the postsynaptic neuron. The exocytosis animation © Madrock24/Shutterstock.com.
To ensure that the transmission is brief and accurately reflects the activity of the presynaptic cell, the synaptic transmitter is either quickly inactivated by enzymes or removed from the synaptic cleft by transporters. The synaptic NT may also activate presynaptic autoreceptors, which can regulate future NT release.
Old-school view: according to Dale’s law, a neuron can only release one NT at a synapse.
New-school view: neurons can release a classical NT and a peptide.
Dale's law proposed that a neuron releases only one NT. However, researchers have found increasing evidence of NT co-release (Svensson et al., 2019). A neuron can store different NTs in separate types of vesicles (Hökfelt et al., 2003). Neurons can also store multiple NTs in the same vesicles (e.g., ATP and glutamate), although they may not release them simultaneously (Merighi et al., 2011; Xia et al., 2009). The large dense-core vesicle (LDCV) graphic from Merighi (2018) was published in Frontiers in Cellular Neuroscience.
Note. The red and green spheres represent co-stored neuropeptides synthesized by the Golgi apparatus in the cell body and transported via microtubules to the axon terminal.
Terminating Neurotransmitter Action
Following exocytosis, NT action is terminated by reuptake and enzymatic degradation. In reuptake, reuptake transporters located in the presynaptic terminal and astrocytes that enclose the synapse return NT molecules to the presynaptic neuron.
Astrocytes transport amino acid NTs (e.g., GABA and glutamate) from the synaptic cleft. Astrocyte glutamate transport graphic from Malik and Willnow (2019) published in the Molecular Journal of International Sciences.
Astrocytes also remove monoamines from synapses. Graphic © Blamb/Shutterstock.com.
In enzymatic degradation, enzymes located in the synaptic cleft and the cytoplasm of the presynaptic neuron's terminal button split neurotransmitter molecules apart (e.g., acetylcholine). These include acetylcholine esterase (AChE), catechol-o-methyltransferase (COMT), and monoamine oxidase (MAO). Graphic © Designua/Shutterstock.com.
The removal mechanism table © Purves (2018).
Extra-Synaptic Transmission: Think Outside the Cleft
Neurons release NTs outside of classical synapses. These mechanisms include release from terminal buttons into the extracellular space, axonal varicosities, and retrograde transmission.
Volume transmission involves NT release and eventual binding to a receptor outside the synaptic cleft (Coggan et al., 2005). Neurons may release NTs from an axon terminal, axonal varicosities, or dendrites. Graphic adapted from the American Scientist.
Axons can release NTs into the extracellular space through axonal varicosities (swellings) along their length, analogous to drip irrigation (Breedlove & Watson, 2023). The graphic below, published by Giachello et al. (2012) in Neuroplasticity, shows diagrams of three types of axonal varicosities and corresponding electron microscopic images.
Note. Schematic representation of the three most common varicosities observed in invertebrate neuronal cultures. It is easier to visualize varicosities in invertebrates than in mammals.
Most neurons that release norepinephrine do not do so through terminal buttons on the ends of axonal branches. Instead, they usually release them through axonal varicosities, beadlike swellings of the axonal branches (Carlson & Birkett, 2019, pp. 82-83).
In retrograde transmission, a presynaptic neuron sends a chemical message to the postsynaptic neuron. In response, the postsynaptic neuron synthesizes and distributes an endocannabinoid (e.g., anandamide) or gas (e.g., nitrous oxide) to the presynaptic neuron and its immediate active neighbors.
Neurons synthesize these NTs on demand since vesicles cannot contain them. The endocannabinoid retrograde transmission graphic from Kelly Heim, PhD, Integrative Pharmacology.
Note: The presynaptic neuron (left) releases glutamate, which binds to the postsynaptic neuron's receptor, triggering anandamide synthesis and retrograde transit.
Postsynaptic neurons also synthesize gases like NO.
. . . this gaseous signal has a range of influence that extends well beyond the cell of origin, diffusing a few tens of micrometers from its site of production before it is degraded. This property makes NO a potentially useful agent for coordinating the activities of multiple cells in a localized region and may mediate certain forms of synaptic plasticity that spread within small networks of neurons (Purves, 2018, pp. 142-143).
Picón-Pagès, Garcia-Buendia, & Muñoz (2019) discussed this process in the Molecular Basis of Disease.
Retrograde NTs can bind to membrane-bound receptors or diffuse into the target cell, initiating second messenger production to adjust synaptic efficiency in learning and memory (Breedlove & Watson, 2023).
Neurotransmitter Release Modulation
Modulation is analogous to a volume control knob instead of an on/off switch on an integrated Simaudio stereo amplifier, analog instead of digital.
Axons can influence the amount of NT released when an action potential arrives at an axon terminal through axoaxonic synapses (junctions between two axons).
Axoaxonic synapses do not affect the generation of an action potential, only the amount of neurotransmitter distributed. In presynaptic facilitation, a neuron increases the presynaptic neuron's neurotransmitter release by delivering a neurotransmitter that increases calcium ion entry into its terminal button. In presynaptic inhibition, a neuron decreases neurotransmitter release by reducing calcium ion entry. These modulatory effects are confined to a single synapse (Breedlove & Watson, 2023).
Autoreceptors Modulate Neurotransmitter Release
Autoreceptors are metabotropic receptors on the presynaptic membrane (see step 7). When NTs released into the synaptic cleft bind to autoreceptors, this hyperpolarizes the axon terminal button to release less NT when the next action potential arrives.
Electrical synapses communicate information across gap junctions between adjacent membranes using ions. Gap junctions are narrow spaces between two cells bridged by connexons (protein channels) that allow ions near-instantaneous travel. Gap junction illustration © VectorMine/Shutterstock.com.
Electrical synapses are generally symmetrical. As long as the gap junction remains open, ions flow across a 3-nm gap junction into the more negatively charged neuron. Whether neurons are presynaptic or postsynaptic depends on their respective charges. When two neurons are electrically coupled, an action potential in one induces a postsynaptic potential (PSP) in the paired neuron.
Transmission across electrical synapses is nearly instantaneous, compared with the 10-ms or longer delay in chemical synapses. The rapid information transmission that characterizes electrical synapses enables large circuits of neurons to synchronize their activity and simultaneously fire.
Studies in recent years have revealed that electrical synapses are common in every part of the mammalian CNS. When two neurons are electrically coupled, an action potential in the presynaptic neuron causes a small amount of ionic current to flow across the gap junction channels into the other neuron. This current causes an electrically mediated postsynaptic potential (PSP) in the second neuron. Note that, because most electrical synapses are bidirectional, when that second neuron generates an action potential, it will in turn induce a PSP in the first neuron (Bear, Connors, & Paradiso,, 2020, p. 113).
Neurons that secrete hormones use electrical synapses to release their chemical messengers simultaneously. Electrical synapses are uncommon in the mature nervous system but are abundant in the developing CNS. This synapse synchronizes local networks of neurons (Purves, 2018). Neonatal brains may use gap junctions to activate many neurons at once.
Gap junctions may be a preliminary step toward developing chemical synapses between these neurons, eventually replacing their electrical synapses. Prenatally and postnatally, gap junctions enable nearby neurons to coordinate their development by sharing electrical and chemical communications (Bear, Connors, & Paradiso, 2020; Breedlove & Watson, 2023).
Electrical synapses resemble action potential conduction along the axon. Unlike chemical synapses which have a delay on the order of a millisecond, electrical synapses operate with virtually no time delay. This quick transmission is why electrical synapses are often present in neural circuits controlling escape behaviors in invertebrates. Additionally, they are found in systems where multiple fibers need to be activated simultaneously, such as controlling eye movements (Breedlove & Watson, 2023). Electrical synapses may also play a role in propagating synchronized seizure discharges in epilepsy (Li et al., 2019).
Vaughn and Haas (2022) argue that electrical synapses function as low-pass filters, which means that electrical synapses can selectively transfer spikes after hyperpolarization. This mechanism essentially offers spike-dependent inhibition. Electrical synapses have other roles, such as encouraging asynchronous firing, enhancing the signal-to-noise ratio, assisting in differentiating unlike inputs or reducing signals by diverting the current.
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acetylcholine esterase (AChE): enzyme responsible for breaking down acetylcholine, a NT, in the synaptic cleft.
action potential: a rapid electrical impulse that travels along a neuron, triggering neurotransmitter release.
amino acid neurotransmitters: NTs derived from amino acids, e.g., glutamate, GABA.
anandamide: endocannabinoid involved in pain, mood, and other functions, acts on cannabinoid receptors.
astrocyte: type of glial cell in the CNS that provides support and nutrients, and modulates synaptic transmission.
autoreceptors: receptors on presynaptic cells that detect and modulate the release of the neuron's own NTs.
axoaxonic synapse: synapse between the axon of one neuron and the axon terminal of another.
axodendritic synapse: a synapse between one neuron's axon and another's dendrite.
axon terminal: the endpoint of a neuron's axon where synaptic vesicles release NTs.
axonal varicosities: swellings along axons containing NTs; act as release sites.
axosomatic synapse: synapse between one neuron's axon and another's soma.
catechol-o-methyltransferase (COMT): an enzyme that breaks down catecholamines like dopamine and epinephrine.
chemical synapse: synapse where signal transmission involves the release of chemical NTs.
connexons: protein complexes that form channels in gap junctions, allowing ions and small molecules to pass.
Dale’s law: the principle that a neuron synthesizes and releases the same NTs at all its synapses.
dendrite: branched extensions of a neuron that receive signals from other neurons.
dendritic spine: a small protrusion from a dendrite that receives input from a single synapse.
depolarization: a decrease in membrane potential, making the inside of the cell more positive; often precedes action potential.
electrical synapse: a direct connection between two neurons that allows for rapid signal transmission via gap junctions.
endocannabinoids: endogenous compounds that bind to cannabinoid receptors, involved in various physiological processes.
enzymatic degradation: breakdown of NTs by enzymes.
exocytosis: releasing substances (e.g., NTs) from a cell via vesicles.
extra-synaptic transmission: neurotransmission outside the traditional synapse, potentially affecting neighboring neurons.
gamma-aminobutyric acid (GABA): the main inhibitory NT in the CNS.
gap junctions: connections between cells allowing direct electrical and chemical communication.
glutamate: the main excitatory NT in the CNS.
Golgi apparatus: the cellular organelle involved in protein modification and sorting.
hyperpolarization: increase in membrane potential, making the inside of the cell more negative; inhibits action potential.
large dense-core vesicle: a type of vesicle that contains peptides and biogenic amines found in neurons and neuroendocrine cells.
modulation: alteration of strength or timing of signals, often via other NTs or neuromodulators.
monoamine oxidase (MAO): an enzyme that degrades monoamines, including many NTs.
monoamines: a group ofNTs containing one amino group, e.g., serotonin, dopamine.
nitrous oxide (NO): gaseous signaling molecule in the nervous system; acts as a retrograde NT.
peptide: a short chain of amino acids, often functioning as a NT or hormone.
postsynaptic neuron: the neuron receiving a signal at a synapse.
presynaptic facilitation: the process of enhancing NT release from the presynaptic neuron.
presynaptic inhibition: the process of reducing NT release from the presynaptic neuron.
presynaptic membrane: the membrane of the neuron releasing a NT at a synapse.
presynaptic neuron: the neuron sending a signal at a synapse.
retrograde transmission: signaling backward, i.e., from postsynaptic to presynaptic neuron.
signal-to-noise ratio: a measure of signal strength relative to background noise in neural communication.
small, clear vesicles: membrane-bound structures containing classical NTs, such as amino acids and acetylcholine.
synaptic vesicles: small membrane-bound structures containing NTs, released into the synaptic cleft.
volume transmission: the diffusion of signaling molecules not restricted to the synaptic cleft, affecting a larger tissue volume.
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