Chemical synapses are biological junctions through whichneurons' signals can be sent to each other and to non-neuronal cells such as those inmuscles orglands. Chemical synapses allow neurons to formcircuits within thecentral nervous system. They are crucial to thebiological computations that underlieperception andthought. They allow thenervous system to connect to and control other systems of the body.

At a chemical synapse, one neuron releasesneurotransmittermolecules into a small space (thesynaptic cleft) that is adjacent to the postsynaptic cell (e.g., another neuron). The neurotransmitter molecules are contained within small sacs calledsynaptic vesicles, and are released into the synaptic cleft byexocytosis. These molecules then bind toneurotransmitter receptors on the postsynaptic cell. Finally, to terminate its action, the neurotransmitter is cleared from the cleft through one of several mechanisms, including enzymatic degradation orre-uptake, byspecific transporters, either into the presynaptic cell or toneuroglia.

Theadulthumanbrain is estimated to contain from 10¹⁴ to 5 × 10¹⁴ (100–500 trillion) synapses.^[1] Every cubic millimeter ofcerebral cortex contains roughly a billion (short scale, i.e. 10⁹) of them.^[2] The number of synapses in the humancerebral cortex has separately been estimated at 0.15 quadrillion (150 trillion)^[3]

The word "synapse" was introduced by SirCharles Scott Sherrington in 1897.^[4] Chemical synapses are not the only type of biologicalsynapse:electrical andimmunological synapses also exist. Without a qualifier, however, "synapse" commonly refers to chemical synapses.

Synapses are functional connections between neurons, or between neurons and other types of cells.^[5][6] A typical neuron gives rise to several thousand synapses, although there are some types that make far fewer.^[7] Most synapses connectaxons todendrites,^[8][9] but there are also other types of connections, including axon-to-cell-body, axon-to-axon,^[10][11] anddendrite-to-dendrite.^[9] Synapses are generally too small to be recognizable using alight microscope except as points where the membranes of two cells appear to touch, but their cellular elements can be visualized clearly using anelectron microscope.

Chemical synapses pass information directionally from a presynaptic cell to a postsynaptic cell and are therefore asymmetric in structure and function. The presynapticaxon terminal, or synapticbouton, is a specialized area within the axon of the presynaptic cell that containsneurotransmitters enclosed in small membrane-bound spheres calledsynaptic vesicles (as well as a number of other supporting structures and organelles, such asmitochondria andendoplasmic reticulum). Some synaptic vesicles are docked at the presynapticplasma membrane at regions calledactive zones.

Immediately opposite is a region of the postsynaptic cell containing neurotransmitterreceptors; for synapses between two neurons the postsynaptic region may be found on the dendrites or cell body. Immediately behind the postsynaptic membrane is an elaborate complex of interlinked proteins called thepostsynaptic density (PSD).

Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors and modulating the activity of these receptors. The receptors and PSDs are often found in specialized protrusions from the main dendritic shaft calleddendritic spines.

Synapses may be described as symmetric or asymmetric. When examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Asymmetric synapses are typically excitatory. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain a prominent postsynaptic density. Symmetric synapses are typically inhibitory.

Thesynaptic cleft—also calledsynaptic gap—is a gap between the pre- and postsynaptic cells that is about 20 nm (0.02 μ) wide.^[12] The small volume of the cleft allows neurotransmitter concentration to be raised and lowered rapidly.^[13]

Anautapse is a chemical (or electrical) synapse formed when the axon of one neuron synapses with its own dendrites.

Some authors consider signal transmission at a chemical synapse as a special case ofparacrine signaling.^[14], while others treat it a separate signaling mechanism.^[15]

Here is a summary of the sequence of events that take place in synaptic transmission from a presynaptic neuron to a postsynaptic cell. Each step is explained in more detail below. Note that with the exception of the final step, the entire process may run only a few hundred microseconds, in the fastest synapses.^[16]

1. The process begins with a wave of electrochemical excitation called anaction potential traveling along the membrane of the presynaptic cell, until it reaches the synapse.
2. The electricaldepolarization of the membrane at the synapse causes channels to open that are permeable to calcium ions.
3. Calcium ions flow through the presynaptic membrane, rapidly increasing the calcium concentration in the interior.
4. The high calcium concentration activates a set of calcium-sensitive proteins attached tovesicles that contain aneurotransmitter chemical.
5. These proteins change shape, causing the membranes of some "docked" vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter contents into the synaptic cleft, the narrow space between the membranes of the pre- and postsynaptic cells.
6. The neurotransmitter diffuses within the cleft. Some of it escapes, but some of it binds tochemical receptor molecules located on the membrane of the postsynaptic cell.
7. The binding of neurotransmitter causes the receptor molecule to beactivated in some way. Several types of activation are possible, as described in more detail below. In any case, this is the key step by which the synaptic process affects the behavior of the postsynaptic cell.
8. Due tothermal vibration, the motion of atoms, vibrating about their equilibrium positions in a crystalline solid, neurotransmitter molecules eventually break loose from the receptors and drift away.
9. The neurotransmitter is either reabsorbed by the presynaptic cell, and then repackaged for future release, or else it is broken down metabolically.

The release of a neurotransmitter is triggered by the arrival of a nerve impulse (oraction potential) and occurs through an unusually rapid process of cellular secretion (exocytosis). Within the presynaptic nerve terminal,vesicles containing neurotransmitter are localized near the synaptic membrane. The arriving action potential produces an influx ofcalcium ions throughvoltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current).^[17] Calcium ions then bind tosynaptotagmin proteins found within the membranes of the synaptic vesicles, allowing the vesicles to fuse with the presynaptic membrane.^[18] The fusion of a vesicle is astochastic process, leading to frequent failure of synaptic transmission at the very small synapses that are typical for thecentral nervous system. Large chemical synapses (e.g. theneuromuscular junction), on the other hand, have a synaptic release probability, in effect, of 1.Vesicle fusion is driven by the action of a set of proteins in the presynaptic terminal known asSNAREs. As a whole, the protein complex or structure that mediates the docking and fusion of presynaptic vesicles is called the active zone.^[19] The membrane added by the fusion process is later retrieved byendocytosis andrecycled for the formation of fresh neurotransmitter-filled vesicles.

An exception to the general trend of neurotransmitter release by vesicular fusion is found in the type II receptor cells of mammaliantaste buds. Here the neurotransmitterATP is released directly from the cytoplasm into the synaptic cleft via voltage gated channels.^[20]

Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules. Receptors can respond in either of two general ways. First, the receptors may directly openligand-gated ion channels in the postsynaptic cell membrane, causing ions to enter or exit the cell and changing the localtransmembrane potential.^[16] The resulting change involtage is called apostsynaptic potential. In general, the result isexcitatory in the case ofdepolarizing currents, andinhibitory in the case ofhyperpolarizing currents. Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct the postsynaptic current(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse. The second way a receptor can affect membrane potential is by modulating the production ofchemical messengers inside the postsynaptic neuron. These second messengers can then amplify the inhibitory or excitatory response to neurotransmitters.^[16]

After a neurotransmitter molecule binds to a receptor molecule, it must be removed to allow for the postsynaptic membrane to continue to relay subsequentEPSPs and/orIPSPs. This removal can happen through one or more processes:

• The neurotransmitter may diffuse away due to thermally-induced oscillations of both it and the receptor, making it available to be broken down metabolically outside the neuron or to be reabsorbed.^[21]
• Enzymes within the subsynaptic membrane may inactivate/metabolize the neurotransmitter.
• Reuptake pumps may actively pump the neurotransmitter back into the presynapticaxon terminal for reprocessing and re-release following a later action potential.^[21]

The strength of a synapse has been defined byBernard Katz as the product of (presynaptic) release probabilitypr, quantal sizeq (the postsynaptic response to the release of a single neurotransmitter vesicle, a 'quantum'), andn, the number of release sites. "Unitary connection" usually refers to an unknown number of individual synapses connecting a presynaptic neuron to a postsynaptic neuron. The amplitude of postsynaptic potentials (PSPs) can be as low as 0.4 mV to as high as 20 mV.^[22] The amplitude of a PSP can be modulated byneuromodulators or can change as a result of previous activity. Changes in the synaptic strength can be short-term, lasting seconds to minutes, or long-term (long-term potentiation, or LTP), lasting hours. Learning and memory are believed to result from long-term changes in synaptic strength, via a mechanism known assynaptic plasticity.

Desensitization of the postsynaptic receptors is a decrease in response to the same neurotransmitter stimulus. It means that the strength of a synapse may in effect diminish as a train of action potentials arrive in rapid succession – a phenomenon that gives rise to the so-called frequency dependence of synapses. The nervous system exploits this property for computational purposes, and can tune its synapses through such means asphosphorylation of the proteins involved.

Synaptic transmission can be changed by previous activity. These changes are called synaptic plasticity and may result in either a decrease in the efficacy of the synapse, called depression, or an increase in efficacy, called potentiation. These changes can either be long-term or short-term. Forms ofshort-term plasticity includesynaptic fatigue or depression andsynaptic augmentation. Forms oflong-term plasticity includelong-term depression andlong-term potentiation. Synaptic plasticity can be either homosynaptic (occurring at a single synapse) or heterosynaptic (occurring at multiple synapses).

Homosynaptic plasticity (or also homotropic modulation) is a change in the synaptic strength that results from the history of activity at a particular synapse. This can result from changes in presynaptic calcium as well as feedback onto presynaptic receptors, i.e. a form ofautocrine signaling. Homosynaptic plasticity can affect the number and replenishment rate of vesicles or it can affect the relationship between calcium and vesicle release. Homosynaptic plasticity can also be postsynaptic in nature. It can result in either an increase or decrease in synaptic strength.

One example is neurons of thesympathetic nervous system (SNS), which releasenoradrenaline, which, besides affecting postsynaptic receptors, also affects presynapticα2-adrenergic receptors, inhibiting further release of noradrenaline.^[23] This effect is utilized withclonidine to perform inhibitory effects on the SNS.

Heterosynaptic plasticity (or also heterotropic modulation) is a change in synaptic strength that results from the activity of other neurons. Again, the plasticity can alter the number of vesicles or their replenishment rate or the relationship between calcium and vesicle release. Additionally, it could directly affect calcium influx. Heterosynaptic plasticity can also be postsynaptic in nature, affecting receptor sensitivity.

One example is again neurons of thesympathetic nervous system, which releasenoradrenaline, which, in addition, generates an inhibitory effect on presynaptic terminals of neurons of theparasympathetic nervous system.^[23]

In general, if anexcitatory synapse is strong enough, anaction potential in the presynaptic neuron will trigger an action potential in the postsynaptic cell. In many cases theexcitatory postsynaptic potential (EPSP) will not reach thethreshold for eliciting an action potential. When action potentials from multiple presynaptic neurons fire simultaneously, or if a single presynaptic neuron fires at a high enough frequency, the EPSPs can overlap and summate. If enough EPSPs overlap, the summated EPSP can reach the threshold for initiating an action potential. This process is known as summation, and can serve as a high pass filter for neurons.^[24]

On the other hand, a presynaptic neuron releasing an inhibitory neurotransmitter, such asGABA, can cause aninhibitory postsynaptic potential (IPSP) in the postsynaptic neuron, bringing themembrane potential farther away from the threshold, decreasing its excitability and making it more difficult for the neuron to initiate an action potential. If an IPSP overlaps with an EPSP, the IPSP can in many cases prevent the neuron from firing an action potential. In this way, the output of a neuron may depend on the input of many different neurons, each of which may have a different degree of influence, depending on the strength and type of synapse with that neuron.John Carew Eccles performed some of the important early experiments on synaptic integration, for which he received theNobel Prize for Physiology or Medicine in 1963.

When a neurotransmitter is released at a synapse, it reaches its highest concentration inside the narrow space of the synaptic cleft, but some of it is certain to diffuse away before being reabsorbed or broken down. If it diffuses away, it has the potential to activate receptors that are located either at other synapses or on the membrane away from any synapse. The extrasynaptic activity of a neurotransmitter is known asvolume transmission.^[25] It is well established that such effects occur to some degree, but their functional importance has long been a matter of controversy.^[26]

Recent work indicates that volume transmission may be the predominant mode of interaction for some special types of neurons. In the mammalian cerebral cortex, a class of neurons calledneurogliaform cells can inhibit other nearby cortical neurons by releasing the neurotransmitter GABA into the extracellular space.^[27] GABA released from neurogliaform cells into the extracellular space also acts on surroundingastrocytes, assigning a role for volume transmission in the control of ionic and neurotransmitter homeostasis.^[28] Approximately 78% of neurogliaform cell boutons do not form classical synapses. This may be the first definitive example of neurons communicating chemically where classical synapses are not present.^[27]

Anelectrical synapse is an electricallyconductive link between two abuttingneurons that is formed at a narrow gap between the pre- and postsynapticcells, known as agap junction. At gap junctions, cells approach within about 3.5 nm of each other, rather than the 20 to 40 nm distance that separates cells at chemical synapses.^[29][30] As opposed to chemical synapses, the postsynaptic potential in electrical synapses is not caused by the opening of ion channels by chemical transmitters, but rather by direct electrical coupling between both neurons. Electrical synapses are faster than chemical synapses.^[13] Electrical synapses are found throughout the nervous system, including in theretina, thereticular nucleus of the thalamus, theneocortex, and in thehippocampus.^[31] While chemical synapses are found between both excitatory and inhibitory neurons, electrical synapses are most commonly found between smaller local inhibitory neurons. Electrical synapses can exist between two axons, two dendrites, or between an axon and a dendrite.^[32][33] In somefish andamphibians, electrical synapses can be found within the same terminal of a chemical synapse, as inMauthner cells.^[34]

One of the most important features of chemical synapses is that they are the site of action for the majority ofpsychoactive drugs. Synapses are affected by drugs, such as curare, strychnine, cocaine, morphine, alcohol, LSD, risperidone, and countless others. These drugs have different effects on synaptic function, and often are restricted to synapses that use a specific neurotransmitter. For example,curare is a poison that stopsacetylcholine from depolarizing the postsynaptic membrane, causingparalysis.Strychnine blocks the inhibitory effects of the neurotransmitterglycine, which causes the body to pick up and react to weaker and previously ignored stimuli, resulting in uncontrollablemuscle spasms.Morphine acts on synapses that useendorphin neurotransmitters, andalcohol increases the inhibitory effects of the neurotransmitterGABA.LSD interferes with synapses that use the neurotransmitterserotonin.Risperidone is a blocker of various receptors including several dopamine and serotonin receptors, and it can bind with high affinity to some types of serotonin receptors.Cocaine blocks reuptake ofdopamine and therefore increases its effects.

During the 1950s,Bernard Katz andPaul Fatt observed spontaneous miniature synaptic currents at the frogneuromuscular junction.^[35] Based on these observations, they developed the 'quantal hypothesis' that is the basis for our current understanding of neurotransmitter release asexocytosis and for which Katz received theNobel Prize in Physiology or Medicine in 1970.^[36] In the late 1960s,Ricardo Miledi and Katz advanced the hypothesis that depolarization-induced influx of calcium ions triggersexocytosis.

Sir Charles Scott Sherringtonin coined the word 'synapse' and the history of the word was given by Sherrington in a letter he wrote to John Fulton:

'I felt the need of some name to call the junction between nerve-cell and nerve-cell... I suggested using "syndesm"... He [Sir Michael Foster ] consulted his Trinity friendVerrall, theEuripidean scholar, about it, and Verrall suggested "synapse" (from the Greek "clasp").'–Charles Scott Sherrington^[4]

• Acclimatisation (neurons)
• Neuroscience
• Neurexin
• Ribbon synapse

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• Llinás R, Sugimori M, Simon SM (April 1982)."Transmission by presynaptic spike-like depolarization in the squid giant synapse".Proc. Natl. Acad. Sci. U.S.A.79 (7):2415–9.Bibcode:1982PNAS...79.2415L.doi:10.1073/pnas.79.7.2415.PMC 346205.PMID 6954549.

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