View source for Synapse

{{Short description|Structure connecting neurons in the nervous system}}
{{About|synapses of the nervous system||3=Synapse (disambiguation)}}
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[[Image:Synapse figure.png|right|thumb|400px|Diagram of a chemical synaptic connection]]

In the [[nervous system]], a '''synapse'''<ref name="Foster_1897">{{cite book| vauthors = Foster M, Sherrington CS |title=Textbook of Physiology | volume = 3 |date=1897|publisher=Macmillan|location=London|page=929|edition=7th | isbn = 978-1-4325-1085-5 }}</ref> is a structure that allows a [[neuron]] (or nerve cell) to pass an electrical or chemical [[Cell signaling|signal]] to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending on the mechanism of signal transmission between neurons. In the case of [[electrical synapse]]s, neurons are coupled bidirectionally with each other through [[gap junction]]s and have a connected cytoplasmic milieu.<ref>{{Cite journal |last=Bennett |first=M. V. L. |date=1966 |title=PHYSIOLOGY OF ELECTROTONIC JUNCTIONS* |url=https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1966.tb50178.x |journal=Annals of the New York Academy of Sciences |language=en |volume=137 |issue=2 |pages=509–539 |doi=10.1111/j.1749-6632.1966.tb50178.x |pmid=5229812 |bibcode=1966NYASA.137..509B |issn=0077-8923|url-access=subscription }}</ref><ref>{{Cite book |title=Principles of neural science |date=2013 |publisher=McGraw-Hill |isbn=978-0-07-139011-8 |editor-last=Kandel |editor-first=Eric R. |edition=5th |location=New York}}</ref><ref>{{Cite book |title=Neuroscience |date=2004 |publisher=Sinauer Associates |isbn=978-0-87893-725-7 |editor-last=Purves |editor-first=Dale |edition=3rd |location=Sunderland, Mass |editor-last2=Williams |editor-first2=Stephen Mark}}</ref> These types of synapses are known to produce synchronous network activity in the brain,<ref>{{Cite journal |last1=Bennett |first1=Michael V.L |last2=Zukin |first2=R.Suzanne |date=2004 |title=Electrical Coupling and Neuronal Synchronization in the Mammalian Brain |url=https://linkinghub.elsevier.com/retrieve/pii/S0896627304000431 |journal=Neuron |volume=41 |issue=4 |pages=495–511 |doi=10.1016/s0896-6273(04)00043-1 |pmid=14980200 |issn=0896-6273|doi-access=free }}</ref> but can also result in complicated, chaotic network level dynamics.<ref>{{Cite journal |last1=Makarenko |first1=Vladimir |last2=Llinás |first2=Rodolfo |date=1998-12-22 |title=Experimentally determined chaotic phase synchronization in a neuronal system |journal=Proceedings of the National Academy of Sciences |language=en |volume=95 |issue=26 |pages=15747–15752 |doi=10.1073/pnas.95.26.15747 |doi-access=free |issn=0027-8424 |pmc=28115 |pmid=9861041|bibcode=1998PNAS...9515747M }}</ref><ref>{{Cite journal |last1=Korn |first1=Henri |last2=Faure |first2=Philippe |date=2003 |title=Is there chaos in the brain? II. Experimental evidence and related models |url=https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2003.09.011/ |journal=Comptes Rendus. Biologies |language=fr |volume=326 |issue=9 |pages=787–840 |doi=10.1016/j.crvi.2003.09.011 |pmid=14694754 |issn=1768-3238|url-access=subscription }}</ref> Therefore, signal directionality cannot always be defined across electrical synapses.<ref>{{Cite journal |last1=Connors |first1=Barry W. |last2=Long |first2=Michael A. |date=2004-07-21 |title=Electrical Synapses in the Mammalian Brain |url=https://www.annualreviews.org/doi/10.1146/annurev.neuro.26.041002.131128 |journal=Annual Review of Neuroscience |language=en |volume=27 |issue=1 |pages=393–418 |doi=10.1146/annurev.neuro.26.041002.131128 |issn=0147-006X|url-access=subscription }}</ref>

[[Chemical synapse]]s, on the other hand, communicate through neurotransmitters released from the presynaptic neuron into the synaptic cleft. Upon release, these neurotransmitters bind to specific receptors on the postsynaptic membrane, inducing an electrical or chemical response in the target neuron. This mechanism allows for more complex modulation of neuronal activity compared to electrical synapses, contributing significantly to the [[Plasticity (brain)|plasticity]] and adaptable nature of neural circuits.<ref>{{Cite journal |last=Apodaca |first=Richard L. |date=2006-09-08 |title=Chemical Reviews on Wikipedia |url=https://doi.org/10.59350/t7n8f-bm508 |access-date=2025-02-02 |website=doi.org|doi=10.59350/t7n8f-bm508 |doi-access=free }}</ref>

Synapses are essential for the transmission of neuronal impulses from one neuron to the next,<ref name="Perea_2009" /> playing a key role in enabling rapid and direct communication by creating circuits. In addition, a synapse serves as a junction where both the transmission and processing of information occur, making it a vital means of communication between neurons.<ref name="Südhof_2021">{{cite journal | vauthors = Südhof TC | title = The cell biology of synapse formation | journal = The Journal of Cell Biology | volume = 220 | issue = 7 | pages = e202103052 | date = July 2021 | pmid = 34086051 | pmc = 8186004 | doi = 10.1083/jcb.202103052 }}</ref>

At the synapse, the [[plasma membrane]] of the signal-passing neuron (the ''presynaptic'' neuron) comes into close [[apposition]] with the membrane of the target (''postsynaptic'') cell. Both the presynaptic and postsynaptic sites contain extensive arrays of [[Molecular biology|molecular machinery]] that link the two membranes together and carry out the signaling process. In many synapses, the presynaptic part is located on the [[Axon terminal|terminals]] of [[axon]]s and the postsynaptic part is located on a [[dendrite]] or [[soma (biology)|soma]]. [[Astrocyte]]s also exchange information with the synaptic neurons, responding to synaptic activity and, in turn, regulating [[neurotransmission]].<ref name="Perea_2009">{{cite journal | vauthors = Perea G, Navarrete M, Araque A | title = Tripartite synapses: astrocytes process and control synaptic information | journal = Trends in Neurosciences | volume = 32 | issue = 8 | pages = 421–431 | date = August 2009 | pmid = 19615761 | doi = 10.1016/j.tins.2009.05.001 | publisher = [[Cell Press]] | s2cid = 16355401 }}</ref> Synapses (at least chemical synapses) are stabilized in position by synaptic adhesion molecules (SAMs)[https://link.springer.com/referenceworkentry/10.1007/978-3-540-29678-2_5807] projecting from both the pre- and post-synaptic neuron and sticking together where they overlap; SAMs may also assist in the generation and functioning of synapses.<ref>{{cite journal | vauthors = Missler M, Südhof TC, Biederer T | title = Synaptic cell adhesion | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 4 | pages = a005694 | date = April 2012 | pmid = 22278667 | pmc = 3312681 | doi = 10.1101/cshperspect.a005694 }}</ref> Moreover, SAMs coordinate the formation of synapses, with various types working together to achieve the remarkable specificity of synapses.<ref name="Südhof_2021" /><ref>{{cite journal | vauthors = Hale WD, Südhof TC, Huganir RL | title = Engineered adhesion molecules drive synapse organization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 120 | issue = 3 | pages = e2215905120 | date = January 2023 | pmid = 36638214 | pmc = 9934208 | doi = 10.1073/pnas.2215905120 | doi-access = free | bibcode = 2023PNAS..12015905H }}</ref> In essence, SAMs function in both [[Excitatory synapse|excitatory]] and [[inhibitory synapses]], likely serving as the mediator for signal transmission.<ref name="Südhof_2021" />

Many mental illnesses are thought to be caused by [[synaptopathy]].

== History ==
[[Santiago Ramón y Cajal]] proposed that neurons are not continuous throughout the body, yet still communicate with each other, an idea known as the [[neuron doctrine]].<ref>{{cite book | vauthors = Elias LJ, Saucier DM |title=Neuropsychology: Clinical and Experimental Foundations |year=2006 |publisher=[[Pearson Education|Pearson/Allyn & Bacon]] |location=Boston |isbn=978-0-20534361-4 |oclc=61131869 |lccn=2005051341}}</ref> The word "synapse" was introduced in 1897 by the English neurophysiologist [[Charles Scott Sherrington|Charles Sherrington]] in [[Michael Foster (physiologist)|Michael Foster]]'s ''Textbook of Physiology''.<ref name="Foster_1897" /> Sherrington struggled to find a good term that emphasized a union between two ''separate'' elements, and the actual term "synapse" was suggested by the English classical scholar [[Arthur Woollgar Verrall]], a friend of Foster.<ref name="OEtymDsynapse">{{OEtymD|synapse}}</ref><ref>{{cite journal | vauthors = Tansey EM | title = Not committing barbarisms: Sherrington and the synapse, 1897 | journal = Brain Research Bulletin | volume = 44 | issue = 3 | pages = 211–212 | year = 1997 | pmid = 9323432 | doi = 10.1016/S0361-9230(97)00312-2 | publisher = [[Elsevier]] | quote = The word synapse first appeared in 1897, in the seventh edition of Michael Foster's ''Textbook of Physiology''. | s2cid = 40333336 }}</ref> The word was derived from the [[Ancient Greek|Greek]] ''synapsis'' ({{lang|grc|σύναψις}}), meaning "conjunction", which in turn derives from ''synaptein'' ({{lang|grc|συνάπτειν}}), from ''syn'' ({{lang|grc|σύν}}) "together" and ''haptein'' ({{lang|grc|ἅπτειν}}) "to fasten".<ref name="OEtymDsynapse"/><ref>{{LSJ|su/nayis|σύναψις}}, {{LSJ|suna/ptw|συνάπτειν}}, {{LSJ|su/n|σύν}}, {{LSJ|a(/ptw|ἅπτειν|ref}}.</ref>

However, while the synaptic gap remained a theoretical construct, and was sometimes reported as a discontinuity between contiguous axonal terminations and dendrites or cell bodies, histological methods using the best light microscopes of the day could not visually resolve their separation which is now known to be about 20&nbsp;nm. It needed the electron microscope in the 1950s to show the finer structure of the synapse with its separate, parallel pre- and postsynaptic membranes and processes, and the cleft between the two.<ref>{{cite journal | vauthors = De Robertis ED, Bennett HS | title = Some features of the submicroscopic morphology of synapses in frog and earthworm | journal = The Journal of Biophysical and Biochemical Cytology | volume = 1 | issue = 1 | pages = 47–58 | date = January 1955 | pmid = 14381427 | pmc = 2223594 | doi = 10.1083/jcb.1.1.47 }}</ref><ref>{{cite journal | vauthors = Palay SL, Palade GE | title = The fine structure of neurons | journal = The Journal of Biophysical and Biochemical Cytology | volume = 1 | issue = 1 | pages = 69–88 | date = January 1955 | pmid = 14381429 | pmc = 2223597 | doi = 10.1083/jcb.1.1.69 }}</ref><ref>{{cite journal | vauthors = Palay SL | title = Synapses in the central nervous system | journal = The Journal of Biophysical and Biochemical Cytology | volume = 2 | issue = 4 Suppl | pages = 193–202 | date = July 1956 | pmid = 13357542 | pmc = 2229686 | doi = 10.1083/jcb.2.4.193 }}</ref>

== Types ==
[[File:Neuro Muscular Junction.png|thumb|An example of chemical synapse by the release of [[neurotransmitter]]s like [[acetylcholine]] or [[glutamic acid]]]]Chemical and electrical synapses are two ways of synaptic transmission.
* In a [[chemical synapse]], electrical activity in the presynaptic neuron is converted (via the activation of [[Voltage-dependent calcium channel|voltage-gated calcium channels]]) into the release of a chemical called a [[neurotransmitter]] that binds to [[neurotransmitter receptor|receptors]] located in the plasma membrane of the postsynaptic cell. The neurotransmitter may initiate an electrical response or a secondary messenger pathway that may either excite or inhibit the postsynaptic neuron. Chemical synapses can be classified according to the neurotransmitter released: [[Glutamic acid|glutamatergic]] (often excitatory), [[gamma-Aminobutyric acid|GABAergic]] (often inhibitory), [[cholinergic]] (e.g. vertebrate [[neuromuscular junction]]), and [[Adrenergic receptor|adrenergic]] (releasing [[norepinephrine]]). Because of the complexity of receptor [[signal transduction]], chemical synapses can have complex effects on the postsynaptic cell.
* In an [[electrical synapse]], the presynaptic and postsynaptic cell membranes are connected by special channels called [[gap junction]]s that are capable of passing an electric current, causing voltage changes in the presynaptic cell to induce voltage changes in the postsynaptic cell.<ref name="Silverthorn_2007" /><ref name="Pereda_2014">{{cite journal | vauthors = Pereda AE | title = Electrical synapses and their functional interactions with chemical synapses | journal = Nature Reviews. Neuroscience | volume = 15 | issue = 4 | pages = 250–263 | date = April 2014 | pmid = 24619342 | pmc = 4091911 | doi = 10.1038/nrn3708 }}</ref> In fact, gap junctions facilitate the direct flow of electrical current without the need for neurotransmitters, as well as small molecules like calcium.<ref>{{cite book | vauthors = Caire MJ, Reddy V, Varacallo M | chapter = Physiology, Synapse |date=2023 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK526047/ | title = StatPearls |access-date=2024-01-01 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30252303 }}</ref> Thus, the main advantage of an electrical synapse is the rapid transfer of signals from one cell to the next.<ref name="Silverthorn_2007">{{cite book | vauthors = Silverthorn DU |title=Human Physiology: An Integrated Approach |edition=4th |year=2007 |publisher=[[Pearson Education|Pearson/Benjamin Cummings]] |location=San Francisco |page=271 |isbn=978-0-8053-6851-2 |oclc=62742632 |lccn=2005056517}}</ref>
* Mixed chemical electrical synapses are synaptic sites that feature both a gap junction and neurotransmitter release.<ref name="pmid4313893">{{cite journal | vauthors = Sotelo C, Palay SL | title = The fine structure of the later vestibular nucleus in the rat. II. Synaptic organization | journal = Brain Research | volume = 18 | issue = 1 | pages = 93–115 | date = February 1970 | pmid = 4313893 | doi = 10.1016/0006-8993(70)90459-2 }}</ref><ref name="pmid6420522">{{cite journal | vauthors = Strausfeld NJ, Bassemir UK | title = Cobalt-coupled neurons of a giant fibre system in Diptera | journal = Journal of Neurocytology | volume = 12 | issue = 6 | pages = 971–91 | date = December 1983 | pmid = 6420522 | doi = 10.1007/BF01153345 | s2cid = 19764983 }}</ref> This combination allows a signal to have both a fast component (electrical) and a slow component (chemical).

The formation of neural circuits in nervous systems appears to heavily depend on the crucial interactions between chemical and electrical synapses. Thus these interactions govern the generation of synaptic transmission.<ref name="Pereda_2014" /> Synaptic communication is distinct from an [[ephaptic coupling]], in which communication between neurons occurs via indirect electric fields.  An [[autapse]] is a chemical or electrical synapse that forms when the axon of one neuron synapses onto dendrites of the same neuron.

=== Excitatory and inhibitory ===

# Excitatory synapse: Enhances the probability of depolarization in postsynaptic neurons and the initiation of an action potential.
# Inhibitory synapse: Diminishes the probability of depolarization in postsynaptic neurons and the initiation of an action potential.
An influx of Na+ driven by excitatory neurotransmitters opens cation channels, depolarizing the postsynaptic membrane toward the action potential threshold. In contrast, inhibitory neurotransmitters cause the postsynaptic membrane to become less depolarized by opening either Cl- or K+ channels, reducing firing. Depending on their release location, the receptors they bind to, and the ionic circumstances they encounter, various transmitters can be either excitatory or inhibitory. For instance, acetylcholine can either excite or inhibit depending on the type of receptors it binds to.<ref name=":0" /> For example, glutamate serves as an excitatory neurotransmitter, in contrast to GABA, which acts as an inhibitory neurotransmitter. Additionally, dopamine is a neurotransmitter that exerts dual effects, displaying both excitatory and inhibitory impacts through binding to distinct receptors.<ref name=":1" />

The [[membrane potential]] prevents Cl- from entering the cell, even when its concentration is much higher outside than inside. The [[reversal potential]] for Cl- in many neurons is quite negative, nearly equal to the [[resting potential]]. Opening Cl- channels tends to buffer the membrane potential, but this effect is countered when the membrane starts to depolarize, allowing more negatively charged Cl- ions to enter the cell. Consequently, it becomes more difficult to depolarize the membrane and excite the cell when Cl- channels are open. Similar effects result from the opening of K+ channels. The significance of inhibitory neurotransmitters is evident from the effects of toxins that impede their activity. For instance, strychnine binds to glycine receptors, blocking the action of glycine and leading to muscle spasms, convulsions, and death.<ref name=":0" />

=== Interfaces ===

Synapses can be classified by the type of cellular structures serving as the pre- and post-synaptic components. The vast majority of synapses in the mammalian nervous system are classical axo-dendritic synapses (axon synapsing upon a dendrite), however, a variety of other arrangements exist. These include but are not limited to{{clarify|date=November 2022}} [[Axo-axonic synapse|axo-axonic]], [[Dendrodendritic synapse|dendro-dendritic]], axo-secretory, axo-ciliary,<ref>{{cite journal | vauthors = Sheu SH, Upadhyayula S, Dupuy V, Pang S, Deng F, Wan J, Walpita D, Pasolli HA, Houser J, Sanchez-Martinez S, Brauchi SE, Banala S, Freeman M, Xu CS, Kirchhausen T, Hess HF, Lavis L, Li Y, Chaumont-Dubel S, Clapham DE | display-authors = 6 | title = A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility | language = English | journal = Cell | volume = 185 | issue = 18 | pages = 3390–3407.e18 | date = September 2022 | pmid = 36055200 | pmc = 9789380 | doi = 10.1016/j.cell.2022.07.026 | s2cid = 251958800 | doi-access = free }}
* University press release: {{cite news |title=Scientists discover new kind of synapse in neurons' tiny hairs |url=https://phys.org/news/2022-09-scientists-kind-synapse-neurons-tiny.html |access-date=19 October 2022 |work=Howard Hughes Medical Institute via phys.org |language=en}}</ref> somato-dendritic, dendro-somatic, and somato-somatic synapses.{{citation needed|date=November 2022}}

In fact, the axon can synapse onto a dendrite, onto a cell body, or onto another axon or axon terminal, as well as into the bloodstream or diffusely into the adjacent nervous tissue.
[[File:Blausen 0843 SynapseTypes.png|thumb|500px|center|Different types of synapses]]

== Conversion of chemical into electrical signals ==
Neurotransmitters are tiny signal molecules stored in membrane-enclosed synaptic vesicles and released via exocytosis. A change in electrical potential in the presynaptic cell triggers the release of these molecules. By attaching to transmitter-gated ion channels, the neurotransmitter causes an electrical alteration in the postsynaptic cell and rapidly diffuses across the synaptic cleft. Once released, the neurotransmitter is swiftly eliminated, either by being absorbed by the nerve terminal that produced it, taken up by nearby glial cells, or broken down by specific enzymes in the synaptic cleft. Numerous Na+-dependent neurotransmitter carrier proteins recycle the neurotransmitters and enable the cells to maintain rapid rates of release.

At chemical synapses, transmitter-gated ion channels play a vital role in rapidly converting extracellular chemical impulses into electrical signals. These channels are located in the postsynaptic cell's plasma membrane at the synapse region, and they temporarily open in response to neurotransmitter molecule binding, causing a momentary alteration in the membrane's permeability. Additionally, transmitter-gated channels are comparatively less sensitive to the membrane potential than voltage-gated channels, which is why they are unable to generate self-amplifying excitement on their own. However, they result in graded variations in membrane potential due to local permeability, influenced by the amount and duration of neurotransmitter released at the synapse.<ref name=":0" />

Recently, mechanical tension, a phenomenon never thought relevant to synapse function has been found to be required for those on hippocampal neurons to fire.<ref name="Joy Nall Emon Lee 2023 p.">{{cite journal |last1=Joy |first1=Md Saddam Hossain |last2=Nall |first2=Duncan L. |last3=Emon |first3=Bashar |last4=Lee |first4=Ki Yun |last5=Barishman |first5=Alexandra |last6=Ahmed |first6=Movviz |last7=Rahman |first7=Saeedur |last8=Selvin |first8=Paul R. |author8-link=Paul R. Selvin |last9=Saif |first9=M. Taher A. |date=2023-12-26 |title=Synapses without tension fail to fire in an in vitro network of hippocampal neurons |journal=Proceedings of the National Academy of Sciences |volume=120 |issue=52 |pages=e2311995120 |doi=10.1073/pnas.2311995120 |doi-access=free |issn=0027-8424 |pmc=10756289 |pmid=38113266|bibcode=2023PNAS..12011995J }}</ref>

== Release of neurotransmitters ==
Neurotransmitters bind to ionotropic receptors on postsynaptic neurons, either causing their opening or closing.<ref name=":1">{{cite web |date=2023 |title=Excitatory and Inhibitory Synaptic Signalling |url=https://teachmephysiology.com/nervous-system/synapses/excitatory-and-inhibitory-signalling-synapses-neurology-teachmephysiology/ |website=TeachMePhysiology |vauthors=Lasica A, Brewer C}}</ref> The variations in the quantities of neurotransmitters released from the presynaptic neuron may play a role in regulating the effectiveness of synaptic transmission. In fact, the concentration of cytoplasmic calcium is involved in regulating the release of neurotransmitters from presynaptic neurons.<ref>{{cite journal |vauthors=Pitman RM |date=September 1984 |title=The versatile synapse |journal=The Journal of Experimental Biology |volume=112 |issue=1 |pages=199–224 |doi=10.1242/jeb.112.1.199 |pmid=6150966|bibcode=1984JExpB.112..199P }}</ref>

The chemical transmission involves several sequential processes:

# Synthesizing neurotransmitters within the presynaptic neuron.
# Loading the neurotransmitters into secretory vesicles.
# Controlling the release of neurotransmitters into the synaptic cleft.
# Binding of neurotransmitters to postsynaptic receptors.
# Ceasing the activity of the released neurotransmitters.<ref>{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK27911/ |vauthors=Holz RW, Fisher SK | chapter = Synaptic Transmission |veditors=Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects.  |date=1999 |publisher=Lippincott-Raven  |edition=6th |language=en |access-date=2024-01-04}}</ref>

== Synaptic polarization ==
The function of neurons depends upon [[cell polarity]]. The distinctive structure of nerve cells allows [[action potential]]s to travel directionally (from dendrites to cell body down the axon), and for these signals to then be received and carried on by post-synaptic neurons or received by effector cells. Nerve cells have long been used as models for cellular polarization, and of particular interest are the mechanisms underlying the polarized localization of synaptic molecules. [[Phosphatidylinositol 4,5-bisphosphate|PIP2]] signaling regulated by [[Inositol monophosphatase|IMPase]] plays an integral role in synaptic polarity.

[[Phosphatidylinositol#Phosphoinositides|Phosphoinositides]] ([[Phosphatidylinositol 4-phosphate|PIP]], PIP2, and [[Phosphatidylinositol (3,4,5)-trisphosphate|PIP3]]) are molecules that have been shown to affect neuronal polarity.<ref>{{cite journal | vauthors = Arimura N, Kaibuchi K | title = Key regulators in neuronal polarity | journal = Neuron | volume = 48 | issue = 6 | pages = 881–884 | date = December 2005 | pmid = 16364893 | doi = 10.1016/j.neuron.2005.11.007 | publisher = Cell Press | doi-access = free }}</ref> A gene (''ttx-7'') was identified in ''[[Caenorhabditis elegans]]'' that encodes ''myo''-inositol monophosphatase (IMPase), an enzyme that produces [[inositol]] by [[dephosphorylation|dephosphorylating]] [[inositol phosphate]]. Organisms with mutant ''ttx-7'' genes demonstrated behavioral and localization defects, which were rescued by expression of IMPase. This led to the conclusion that IMPase is required for the correct localization of synaptic protein components.<ref name="SynapticPolarity">{{cite journal | vauthors = Kimata T, Tanizawa Y, Can Y, Ikeda S, Kuhara A, Mori I | title = Synaptic polarity depends on phosphatidylinositol signaling regulated by myo-inositol monophosphatase in Caenorhabditis elegans | journal = Genetics | volume = 191 | issue = 2 | pages = 509–521 | date = June 2012 | pmid = 22446320 | pmc = 3374314 | doi = 10.1534/genetics.111.137844 | publisher = [[Genetics Society of America]] }}</ref><ref>{{cite journal | vauthors = Tanizawa Y, Kuhara A, Inada H, Kodama E, Mizuno T, Mori I | title = Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans | journal = Genes & Development | volume = 20 | issue = 23 | pages = 3296–3310 | date = December 2006 | pmid = 17158747 | pmc = 1686606 | doi = 10.1101/gad.1497806 | publisher = [[Cold Spring Harbor Laboratory Press]] }}</ref> The ''egl-8'' gene encodes a homolog of [[phospholipase C]]β (PLCβ), an enzyme that cleaves PIP2. When ''ttx-7'' mutants also had a mutant ''egl-8'' gene, the defects caused by the faulty ''ttx-7'' gene were largely reversed. These results suggest that PIP2 signaling establishes polarized localization of synaptic components in living neurons.<ref name="SynapticPolarity" />

== Presynaptic modulation ==
Modulation of [[neurotransmitter]] release by [[G protein-coupled receptor|G-protein-coupled receptors]] (GPCRs) is a prominent presynaptic mechanism for regulation of [[Neurotransmission|synaptic transmission]]. The activation of GPCRs located at the presynaptic terminal, can decrease the probability of neurotransmitter release. This presynaptic depression involves activation of [[Gi alpha subunit|Gi/o]]-type [[G protein|G-proteins]] that mediate different inhibitory mechanisms, including inhibition of [[voltage-gated calcium channel]]s, activation of [[potassium channel]]s, and direct inhibition of the [[vesicle fusion]] process.

[[Cannabinoid#Endocannabinoids|Endocannabinoids]], synthesized in and released from postsynaptic [[neuron]]al elements and their cognate [[Receptor (biochemistry)|receptors]], including the (GPCR) [[Cannabinoid receptor type 1|CB1 receptor]] located at the presynaptic terminal, are involved in this modulation by a [[retrograde signaling]] process, in which these compounds are synthesized in and released from postsynaptic neuronal elements and travel back to the presynaptic terminal to act on the CB1 receptor for short-term or long-term synaptic depression, that causes a short or long lasting decrease in neurotransmitter release.<ref>{{cite book | vauthors = Lovinger DM |chapter=Presynaptic Modulation by Endocannabinoids|date=2008|pages=435–477| veditors = Südhof TC, Starke K |title=Pharmacology of Neurotransmitter Release|series=Handbook of Experimental Pharmacology |publisher=Springer Berlin Heidelberg |language=en |doi=10.1007/978-3-540-74805-2_14 |pmid=18064422 |isbn=9783540748052 |volume=184|issue=184}}</ref>

== Effects of drugs on ligand-gated ion channels ==
Drugs have long been considered crucial targets for transmitter-gated ion channels. The majority of medications utilized to treat schizophrenia, anxiety, depression, and sleeplessness work at chemical synapses, and many of these pharmaceuticals function by binding to transmitter-gated channels. For instance, some drugs like barbiturates and tranquilizers bind to GABA receptors and enhance the inhibitory effect of GABA neurotransmitter. Thus, reduced concentration of GABA enables the opening of Cl- channels.

Furthermore, psychoactive drugs could potentially target many other synaptic signalling machinery components. Neurotransmitter release is a complex process involving various types of transporters and mechanisms for removing neurotransmitters from the synaptic cleft. While Na+-driven carriers play a role, other mechanisms are also involved, depending on the specific neurotransmitter system.{{needs source|date=March 2025}} For example, Prozac is an antidepressant medication that works by preventing the absorption of serotonin neurotransmitter. Also, other antidepressants operate by inhibiting the reabsorption of both serotonin and norepinephrine.<ref name=":0">{{cite book | vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P | chapter = Ion Channels and the Electrical Properties of Membranes |date=2002 | title = Molecular Biology of the Cell | edition = 4th  | chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK26910/ |access-date=2024-01-20 |publisher=Garland Science |language=en }}</ref>

== Biogenesis ==

In nerve terminals, synaptic vesicles are produced quickly to compensate for their rapid depletion during neurotransmitter release. Their biogenesis involves segregating synaptic vesicle membrane proteins from other cellular proteins and packaging those distinct proteins into vesicles of appropriate size. Besides, it entails the endocytosis of synaptic vesicle membrane proteins from the plasma membrane.<ref>{{cite journal |date=1995-09-01 |title=Biogenesis of synaptic vesicles in vitro |journal=The Journal of Cell Biology |volume=130 |issue=5 |pages=1041–1049 |doi=10.1083/jcb.130.5.1041 |issn=0021-9525 |pmc=2120557 |pmid=7544795 | vauthors = Desnos C, Clift-o'Grady L, Kelly RB }}</ref>

<!--from redirect to definition-->'''Synaptoblastic''' and <!--from redirect to definition-->'''synaptoclastic''' refer to synapse-producing and synapse-removing activities within the biochemical signalling chain. This terminology is associated with the <!--from redirect to definition; to become its own article should it pan out-->'''Bredesen Protocol''' for treating [[Alzheimer's disease]], which conceptualizes Alzheimer's as an imbalance between these processes. As of October 2023, studies concerning this protocol remain small and few results have been obtained within a standardized control framework.

== Role in memory ==
{{Main|Hebbian theory}}

=== Potentiation and depression ===
It is widely accepted that the synapse plays a key role in the formation of [[memory]].<ref name=":2" /> The stability of long-term memory can persist for many years; nevertheless, synapses, the neurological basis of memory, are very dynamic.<ref>{{cite journal | vauthors = Yang Y, Lu J, Zuo Y | title = Changes of synaptic structures associated with learning, memory and diseases. | journal = Brain Science Advances | date = December 2018 | volume = 4 | issue = 2 | pages = 99–117 |doi = 10.26599/BSA.2018.2018.9050012 | doi-access = free }}</ref> The formation of synaptic connections significantly depends on activity-dependent synaptic plasticity observed in various synaptic pathways. Indeed, the connection between memory formation and alterations in synaptic efficacy enables the reinforcement of neuronal interactions between neurons. As neurotransmitters activate receptors across the synaptic cleft, the connection between the two neurons is strengthened when both neurons are active at the same time, as a result of the receptor's signaling mechanisms. Memory formation involves complex interactions between neural pathways, including the strengthening and weakening of synaptic connections, which contribute to the storage of information.<ref>{{Cite journal |last=Deason |first=Hilary |date=1966-08-12 |title=Science and Technology Supplements: ''The McGraw-Hill Yearbook of Science and Technology'' . David I. Eggenberger, Exec. Ed. McGraw-Hill, New York, 1966. 461 pp. Illus. $24.; ''McGraw-Hili Modern Men of Science'' . Jay E. Greene, Ed. McGrawHill, New York, 1966. 630 pp. Illus. $19.50.; ''McGraw-Hill Basic Bibliography of Science and Technology'' . David I. Eggenberger, Exec. Ed. McGraw-Hill, New York, 1966. 748 pp. $19.50. |url=https://doi.org/10.1126/science.153.3737.731 |journal=Science |volume=153 |issue=3737 |pages=731 |doi=10.1126/science.153.3737.731 |issn=0036-8075|url-access=subscription }}</ref> This process of synaptic strengthening is known as [[long-term potentiation|long-term potentiation (LTP)]].<ref name=":2">{{cite journal | vauthors = Lynch MA | title = Long-term potentiation and memory | journal = Physiological Reviews | volume = 84 | issue = 1 | pages = 87–136 | date = January 2004 | pmid = 14715912 | doi = 10.1152/physrev.00014.2003 | url = https://zenodo.org/record/896261 }}</ref>

By altering the release of neurotransmitters, the plasticity of synapses can be controlled in the presynaptic cell. The postsynaptic cell can be regulated by altering the function and number of its receptors. Changes in postsynaptic signaling are most commonly associated with a [[NMDA|N-methyl-d-aspartic acid]] receptor (NMDAR)-dependent LTP and [[long-term depression]] (LTD) due to the influx of calcium into the post-synaptic cell, which are the most analyzed forms of plasticity at excitatory synapses.<ref>{{cite journal |vauthors=Krugers HJ, Zhou M, Joëls M, Kindt M |date=October 11, 2011 |title=Regulation of excitatory synapses and fearful memories by stress hormones |journal=Frontiers in Behavioral Neuroscience |publisher=[[Frontiers (publisher)|Frontiers Media SA]] |volume=5 |pages=62 |doi=10.3389/fnbeh.2011.00062 |pmc=3190121 |pmid=22013419 |doi-access=free}}</ref>

=== Mechanism of protein kinase ===
Moreover, Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is best recognized for its roles in the brain, particularly in the neocortex and hippocampal regions because it serves as a ubiquitous mediator of cellular Ca2+ signals. CaMKII is abundant in the nervous system, mainly concentrated in the synapses in the nerve cells. Indeed, CaMKII has been definitively identified as a key regulator of cognitive processes, such as learning, and neural plasticity. The first concrete experimental evidence for the long-assumed function of CaMKII in memory storage was demonstrated

While Ca2+/CaM binding stimulates CaMKII activity, Ca2+-independent autonomous CaMKII activity can also be produced by a number of other processes. CaMKII becomes active by autophosphorylating itself upon Ca2+/calmodulin binding. CaMKII is still active and phosphorylates itself even after Ca2+ is cleaved; as a result, the brain stores long-term memories using this mechanism. Nevertheless, when the CaMKII enzyme is dephosphorylated by a phosphatase enzyme, it becomes inactive, and memories are lost. Hence, CaMKII plays a vital role in both the induction and maintenance of LTP.<ref>{{cite journal | vauthors = Bayer KU, Schulman H | title = CaM Kinase: Still Inspiring at 40 | journal = Neuron | volume = 103 | issue = 3 | pages = 380–394 | date = August 2019 | pmid = 31394063 | pmc = 6688632 | doi = 10.1016/j.neuron.2019.05.033 }}</ref>

=== Synaptic Computation ===
Beyond serving as passive relays, synapses perform complex computations on incoming signals. Models of synaptic computation describe how neurotransmitter release kinetics, receptor subunit composition, and short‑term plasticity endow individual synapses with filtering, gain control, and temporal integration capabilities. Recent connectomic and functional studies—such as those reconstructing the larval zebrafish brainstem circuit—demonstrate that synaptic wiring diagrams can predict behaviorally relevant neural codes, underscoring the computational role of synaptic networks in information processing.<ref>{{Cite journal |last1=Martínez De Fabricius |first1=Ana L. |last2=Maidana |first2=N. |last3=Gómez |first3=N. |last4=Sabater |first4=S. |title=Distribution patterns of benthic diatoms in a Pampean river exposed to seasonal floods: The Cuarto River (Argentina) |date=2003 |url=https://doi.org/10.1023/a:1025857715437 |journal=Biodiversity and Conservation |volume=12 |issue=12 |pages=2443–2454 |doi=10.1023/a:1025857715437 |bibcode=2003BiCon..12.2443M |issn=0960-3115|url-access=subscription }}</ref>

== Experimental models ==
For technical reasons, synaptic structure and function have been historically studied at unusually large [[Model organism|model]] synapses, for example:
* [[Squid giant synapse]]
* [[Neuromuscular junction]] (NMJ), a cholinergic synapse in vertebrates, glutamatergic in insects
* Ciliary calyx in the ciliary ganglion of chicks<ref>{{cite journal | vauthors = Stanley EF | title = The calyx-type synapse of the chick ciliary ganglion as a model of fast cholinergic transmission | journal = Canadian Journal of Physiology and Pharmacology | volume = 70 | issue = Suppl | pages = S73–S77 | date = 1992 | pmid = 1338300 | doi = 10.1139/y92-246 }}</ref>
* [[Calyx of Held]] in the brainstem
* [[Ribbon synapse]] in the retina
* [[Schaffer collateral]] synapses in the [[hippocampus]]. These synapses are small, but their pre- and postsynaptic neurons are well separated (CA3 and CA1, respectively).

== Clinical Relevance ==
Synaptic dysfunction and loss are now recognized as central to the pathophysiology of major neurodegenerative and neurodevelopmental disorders. In Alzheimer’s disease (AD), synapse loss correlates more strongly with cognitive decline than amyloid‑β plaque burden, and emerging biomarkers—such as the YWHAG:NPTX2 ratio in cerebrospinal fluid and plasma—offer prognostic value for AD onset and progression. Synaptic pathology in AD encompasses alterations in glutamatergic transmission, dendritic spine density, and synaptic protein turnover, highlighting synapses both as early indicators of disease and as targets for therapeutic intervention.<ref>{{Cite journal |last1=Terry |first1=Nickolas |last2=Masliah |first2=Alberto |last3=Overk |first3=Cassia |last4=Masliah |first4=Eliezer |date=2019-08-03 |title=Remembering Robert D. Terry at a Time of Change in the World of Alzheimer's Disease |url=https://doi.org/10.3233/jad-190518 |journal=Journal of Alzheimer's Disease |volume=70 |issue=3 |pages=621–628 |doi=10.3233/jad-190518 |pmid=31282421 |issn=1387-2877|pmc=6750985 }}</ref><ref>{{Cite journal |last1=Chen |first1=Yu-Han |last2=Wang |first2=Zhi-Bo |last3=Liu |first3=Xi-Peng |last4=Mao |first4=Zhi-Qi |date=2025-03-19 |title=Cerebrospinal fluid LMO4 as a synaptic biomarker linked to Alzheimer's disease pathology and cognitive decline |url=https://doi.org/10.1177/13872877251326286 |journal=Journal of Alzheimer's Disease |doi=10.1177/13872877251326286 |pmid=40105503 |issn=1387-2877|url-access=subscription }}</ref>

Synaptic disruptions can lead to a variety of negative effects, including impaired learning, memory, and cognitive function.<ref>{{Cite journal |last1=Hayes |first1=Brett K. |last2=Heit |first2=Evan |date=August 2004 |title=Why learning and development can lead to poorer recognition memory |url=https://doi.org/10.1016/j.tics.2004.05.001 |journal=Trends in Cognitive Sciences |volume=8 |issue=8 |pages=337–339 |doi=10.1016/j.tics.2004.05.001 |pmid=15335459 |issn=1364-6613|url-access=subscription }}</ref> In fact, alterations in cell-intrinsic molecular systems or modifications to environmental biochemical processes can lead to synaptic dysfunction. The synapse is the primary unit of information transfer in the nervous system, and correct synaptic contact creation during development is essential for normal brain function. Genetic mutations can disrupt synapse formation and function, contributing to the development of neurodevelopmental and neurodegenerative disorders.<ref>{{Cite journal |last=Südhof |first=Thomas C. |date=2021-07-05 |title=The cell biology of synapse formation |url=https://rupress.org/jcb/article/220/7/e202103052/212258/The-cell-biology-of-synapse-formationMechanisms-of |journal=Journal of Cell Biology |language=en |volume=220 |issue=7 |pages=e202103052 |doi=10.1083/jcb.202103052 |pmid=34086051 |issn=0021-9525|pmc=8186004 }}</ref> However, the precise relationship between specific mutations and disease phenotypes is complex and requires further investigation.

Synaptic defects are causally associated with early appearing neurological diseases, including autism spectrum disorders (ASD), schizophrenia (SCZ), and bipolar disorder (BP). Synaptic dysfunction, or synaptopathy, is often implicated in late-onset neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, but the exact mechanisms contributing to this phenomenon are not fully understood.<ref>{{Cite journal |last1=Missler |first1=M. |last2=Sudhof |first2=T. C. |last3=Biederer |first3=T. |date=2012-04-01 |title=Synaptic Cell Adhesion |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=4 |issue=4 |pages=a005694 |doi=10.1101/cshperspect.a005694 |pmid=22278667 |issn=1943-0264|pmc=3312681 }}</ref> These diseases are identified by a gradual loss in cognitive and behavioral function and a steady loss of brain tissue. Moreover, these deteriorations have been mostly linked to the gradual build-up of protein aggregates in neurons, the composition of which may vary based on the pathology; all have the same deleterious effects on neuronal integrity. Furthermore, the high number of mutations linked to synaptic structure and function, as well as dendritic spine alterations in post-mortem tissue, has led to the association between synaptic defects and neurodevelopmental disorders, such as ASD and SCZ, characterized by abnormal behavioral or cognitive phenotypes.

Nevertheless, due to limited access to human tissue at late stages and a lack of thorough assessment of the essential components of human diseases in the available experimental animal models, it has been difficult to fully grasp the origin and role of synaptic dysfunction in neurological disorders.<ref>{{cite journal |last1=Taoufik |first1=Era |last2=Kouroupi |first2=Georgia |last3=Zygogianni |first3=Ourania |last4=Matsas |first4=Rebecca |date=2018-09-05 |title=Synaptic dysfunction in neurodegenerative and neurodevelopmental diseases: an overview of induced pluripotent stem-cell-based disease models |journal=Open Biology |volume=8 |issue=9 |pages=180138 |doi=10.1098/rsob.180138 |issn=2046-2441 |pmc=6170506 |pmid=30185603}}</ref>

==Additional images==
<gallery>
 Image:Synapse figure.png|Diagram of the synapse. Please see [https://www.learnbio.org/synapse.html learnbio.org] for interactive version.
 Image:Neuron synapse.svg|A typical central nervous system synapse
 Image:Active zone3.JPG|The synapse and synaptic vesicle cycle
 Image:Chemical synapse schema cropped.jpg|Major elements in chemical synaptic transmission
</gallery>

== See also ==

{{col div|colwidth=30em}}
* [[Active zone]]
* [[Autapse]]
* [[Cooperative synapse formation]]
* [[Exocytosis]]
* [[Immunological synapse]]
* [[Neurotransmitter vesicle]]
* [[Neurexin]]
* [[Postsynaptic density]]
* [[Synaptopathy]]
{{colend}}

== References ==
{{Reflist|30em}}

{{Nervous tissue}}
{{Authority control}}

[[Category:Signal transduction]]
[[Category:Neural synapse| ]]