Editing Synaptic plasticity (section)

==Biochemical mechanisms==
Two molecular mechanisms for synaptic plasticity involve the [[NMDA]] and [[AMPA]] glutamate receptors. Opening of NMDA channels (which relates to the level of cellular [[depolarization]]) leads to a rise in post-synaptic Ca<sup>2+</sup> concentration and this has been linked to long-term potentiation, LTP (as well as to protein [[kinase]] activation); strong depolarization of the post-synaptic cell completely displaces the [[magnesium]] ions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg<sup>2+</sup> ions, resulting in less Ca<sup>2+</sup> entering the post-synaptic neuron and lower intracellular Ca<sup>2+</sup> concentrations (which activate protein phosphatases and induce [[long-term depression]], LTD).<ref>Bear MF, Connors BW, and Paradisio MA. 2007. Neuroscience: Exploring the Brain, 3rd ed. Lippincott, Williams & Wilkins</ref>

These activated protein kinases serve to phosphorylate post-synaptic excitatory receptors (e.g. [[AMPA receptor]]s), improving cation conduction, and thereby potentiating the synapse. Also, these signals recruit additional receptors into the post-synaptic membrane, stimulating the production of a modified receptor type, thereby facilitating an influx of calcium. This in turn increases post-synaptic excitation by a given pre-synaptic stimulus. This process can be reversed via the activity of protein phosphatases, which act to dephosphorylate these cation channels.<ref>{{cite journal | vauthors = Soderling TR, Derkach VA | title = Postsynaptic protein phosphorylation and LTP | journal = Trends in Neurosciences | volume = 23 | issue = 2 | pages = 75–80 | date = February 2000 | pmid = 10652548 | doi = 10.1016/S0166-2236(99)01490-3 | s2cid = 16733526 }}</ref>

The second mechanism depends on a [[second messenger]] cascade regulating [[Transcription (genetics)|gene transcription]] and changes in the levels of key proteins such as [[CaMKII]] and PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within the [[dendritic spine]]. These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to the [[plasma membrane]] and phosphorylation of ion channels for enhanced permeability.<ref name="Haining09">
{{cite journal | vauthors = Zhong H, Sia GM, Sato TR, Gray NW, Mao T, Khuchua Z, Huganir RL, Svoboda K | display-authors = 6 | title = Subcellular dynamics of type II PKA in neurons | journal = Neuron | volume = 62 | issue = 3 | pages = 363–74 | date = May 2009 | pmid = 19447092 | pmc = 2702487 | doi = 10.1016/j.neuron.2009.03.013 }}</ref> Localization or compartmentalization of activated proteins occurs in the presence of their given stimulus which creates local effects in the dendritic spine. Calcium influx from NMDA receptors is necessary for the activation of CaMKII. This activation is localized to spines with focal stimulation and is inactivated before spreading to adjacent spines or the shaft, indicating an important mechanism of LTP in that particular changes in protein activation can be localized or compartmentalized to enhance the responsivity of single dendritic spines. Individual dendritic spines are capable of forming unique responses to presynaptic cells.<ref name="Seok-Jin09">
{{cite journal | vauthors = Lee SJ, Escobedo-Lozoya Y, Szatmari EM, Yasuda R | title = Activation of CaMKII in single dendritic spines during long-term potentiation | journal = Nature | volume = 458 | issue = 7236 | pages = 299–304 | date = March 2009 | pmid = 19295602 | pmc = 2719773 | doi = 10.1038/nature07842 | bibcode = 2009Natur.458..299L }}</ref> This second mechanism can be triggered by [[protein phosphorylation]] but takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of these [[second messenger]]s. [[Phosphodiesterase]], for example, breaks down the secondary messenger [[Cyclic adenosine monophosphate|cAMP]], which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron {{Citation needed|date=December 2011}}.

Long-lasting changes in the efficacy of synaptic connections ([[long-term potentiation]], or LTP) between two neurons can involve the making and breaking of synaptic contacts. Genes such as activin ß-A, which encodes a subunit of [[activin A]], are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through the [[Mitogen-activated protein kinase|MAP-kinase pathway]]. By changing the [[F-actin]] [[cytoskeletal]] structure of dendritic spines, spine necks are lengthened producing increased electrical isolation.<ref>{{cite journal | vauthors = Araya R, Jiang J, Eisenthal KB, Yuste R | title = The spine neck filters membrane potentials | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 47 | pages = 17961–6 | date = November 2006 | pmid = 17093040 | pmc = 1693855 | doi = 10.1073/pnas.0608755103 | bibcode = 2006PNAS..10317961A | doi-access = free }}</ref> The end result is long-term maintenance of LTP.<ref name="Synapse">{{cite journal | vauthors = Shoji-Kasai Y, Ageta H, Hasegawa Y, Tsuchida K, Sugino H, Inokuchi K | title = Activin increases the number of synaptic contacts and the length of dendritic spine necks by modulating spinal actin dynamics | journal = Journal of Cell Science | volume = 120 | issue = Pt 21 | pages = 3830–7 | date = November 2007 | pmid = 17940062 | doi = 10.1242/jcs.012450 | doi-access = free }}</ref>

The number of [[ion channel]]s on the post-synaptic membrane affects the strength of the synapse.<ref>
{{cite journal | vauthors = Debanne D, Daoudal G, Sourdet V, Russier M | title = Brain plasticity and ion channels | journal = Journal of Physiology, Paris | volume = 97 | issue = 4–6 | pages = 403–14 | year = 2003 | pmid = 15242652 | doi = 10.1016/j.jphysparis.2004.01.004 | s2cid = 19116187 }}</ref> Research suggests that the density of receptors on post-synaptic membranes changes, affecting the neuron's excitability in response to stimuli. In a dynamic process that is maintained in equilibrium, [[NMDA receptor|N-methyl D-aspartate receptor (NMDA receptor)]] and AMPA receptors are added to the membrane by [[exocytosis]] and removed by [[endocytosis]].<ref name="Shi99">
{{cite journal |author6-link=Karel Svoboda (scientist)| vauthors = Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R | title = Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation | journal = Science | volume = 284 | issue = 5421 | pages = 1811–6 | date = June 1999 | pmid = 10364548 | doi = 10.1126/science.284.5421.1811 | citeseerx = 10.1.1.376.3281 }}</ref><ref name="Song02">
{{cite journal | vauthors = Song I, Huganir RL | title = Regulation of AMPA receptors during synaptic plasticity | journal = Trends in Neurosciences | volume = 25 | issue = 11 | pages = 578–88 | date = November 2002 | pmid = 12392933 | doi = 10.1016/S0166-2236(02)02270-1 | s2cid = 1993509 }}</ref><ref name="PO05">{{cite journal | vauthors = Pérez-Otaño I, Ehlers MD | title = Homeostatic plasticity and NMDA receptor trafficking | journal = Trends in Neurosciences | volume = 28 | issue = 5 | pages = 229–38 | date = May 2005 | pmid = 15866197 | doi = 10.1016/j.tins.2005.03.004 | s2cid = 22901201 | url = http://www.psychiatry.wustl.edu/zorumski/journal%20club/Perez-Otano%20and%20Ehlers%209_23.pdf | access-date = 2007-06-08 | url-status = dead | archive-url = https://web.archive.org/web/20110720121632/http://www.psychiatry.wustl.edu/zorumski/journal%20club/Perez-Otano%20and%20Ehlers%209_23.pdf | archive-date = July 20, 2011 }}</ref> These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity.<ref name="Shi99" /><ref name="PO05" /> Experiments have shown that AMPA receptors are delivered to the synapse through vesicular [[membrane fusion]] with the postsynaptic membrane via the protein kinase CaMKII, which is activated by the influx of calcium through NMDA receptors. CaMKII also improves AMPA ionic conductance through phosphorylation.<ref name="Bear_2007">{{cite book | vauthors = Bear MF | author-link = Mark F. Bear | title = Neuroscience: Exploring the Brain | url = https://archive.org/details/neuroscienceexpl00mark | url-access = registration | publisher = [[Lippincott Williams & Wilkins]] | series = Third Edition | year =2007 | pages =[https://archive.org/details/neuroscienceexpl00mark/page/779 779] | isbn = 978-0-7817-6003-4}}</ref>
When there is high-frequency NMDA receptor activation, there is an increase in the expression of a protein [[PSD-95]] that increases synaptic capacity for AMPA receptors.<ref name="stabilization_plasticity">
{{cite journal | vauthors = Meyer D, Bonhoeffer T, Scheuss V | title = Balance and stability of synaptic structures during synaptic plasticity | journal = Neuron | volume = 82 | issue = 2 | pages = 430–43 | date = April 2014 | pmid = 24742464 | doi = 10.1016/j.neuron.2014.02.031 | doi-access = free }}</ref> This is what leads to a long-term increase in AMPA receptors and thus synaptic strength and plasticity.

If the strength of a synapse is only reinforced by stimulation or weakened by its lack, a [[positive feedback loop]] will develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling and [[metaplasticity]], also exist to provide [[negative feedback]].<ref name="PO05" /> Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down.<ref>
{{cite journal | vauthors = Desai NS, Cudmore RH, Nelson SB, Turrigiano GG | title = Critical periods for experience-dependent synaptic scaling in visual cortex | journal = Nature Neuroscience | volume = 5 | issue = 8 | pages = 783–9 | date = August 2002 | pmid = 12080341 | doi = 10.1038/nn878 | s2cid = 17747903 }}</ref>
  
[[Synaptic scaling]] serves to maintain the strengths of synapses relative to each other, lowering amplitudes of small [[excitatory postsynaptic potential]]s in response to continual excitation and raising them after prolonged blockage or inhibition.<ref name="PO05" /> This effect occurs gradually over hours or days, by changing the numbers of [[NMDA receptor]]s at the synapse (Pérez-Otaño and Ehlers, 2005). [[Metaplasticity]] varies the threshold level at which plasticity occurs, allowing integrated responses to synaptic activity spaced over time and preventing saturated states of LTP and LTD. Since LTP and LTD ([[long-term depression]]) rely on the influx of [[Calcium in biology|Ca<sup>2+</sup>]] through NMDA channels, metaplasticity may be due to changes in NMDA receptors, altered calcium buffering, altered states of kinases or phosphatases and a priming of protein synthesis machinery.<ref name="Abraham97">{{cite journal | vauthors = Abraham WC, Tate WP | title = Metaplasticity: a new vista across the field of synaptic plasticity | journal = Progress in Neurobiology | volume = 52 | issue = 4 | pages = 303–23 | date = July 1997 | pmid = 9247968 | doi = 10.1016/S0301-0082(97)00018-X | s2cid = 33285995 }}</ref> Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs.<ref name="Abbot2000">{{cite journal | vauthors = Abbott LF, Nelson SB | title = Synaptic plasticity: taming the beast | journal = Nature Neuroscience | volume = 3 Suppl | pages = 1178–83 | date = November 2000 | pmid = 11127835 | doi = 10.1038/81453 | s2cid = 2048100 }}</ref>
The neuronal circuitry affected by LTP/LTD and modified by scaling and metaplasticity leads to reverberatory neural circuit development and regulation in a Hebbian manner which is manifested as memory, whereas the changes in neural circuitry, which begin at the level of the synapse, are an integral part in the ability of an organism to learn.<ref>
{{cite journal | vauthors = Cooper SJ | title = Donald O. Hebb's synapse and learning rule: a history and commentary | journal = Neuroscience and Biobehavioral Reviews | volume = 28 | issue = 8 | pages = 851–74 | date = January 2005 | pmid = 15642626 | doi = 10.1016/j.neubiorev.2004.09.009 | s2cid = 40805686 }}</ref>

There is also a specificity element of biochemical interactions to create synaptic plasticity, namely the importance of location. Processes occur at microdomains – such as [[exocytosis]] of AMPA receptors is spatially regulated by the [[t-SNARE]] [[STX4]].<ref>{{cite journal | vauthors = Kennedy MJ, Davison IG, Robinson CG, Ehlers MD | title = Syntaxin-4 defines a domain for activity-dependent exocytosis in dendritic spines | journal = Cell | volume = 141 | issue = 3 | pages = 524–35 | date = April 2010 | pmid = 20434989 | pmc = 2874581 | doi = 10.1016/j.cell.2010.02.042 }}</ref> Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium.<ref name="Seok-Jin09"/>
The spatial gradient of PKA between dendritic spines and shafts is also important for the strength and regulation of synaptic plasticity.<ref name="Haining09"/> It is important to remember that the biochemical mechanisms altering synaptic plasticity occur at the level of individual synapses of a neuron. Since the biochemical mechanisms are confined to these "microdomains," the resulting synaptic plasticity affects only the specific synapse at which it took place.