Editing Retrograde signaling (section)

===Retrograde signaling in long-term potentiation===
{{main|Long-term potentiation}}
As it pertains to LTP, retrograde signaling is a hypothesis describing how events underlying LTP may begin in the [[postsynaptic neuron]] but be propagated to the [[presynaptic neuron]], even though normal [[synaptic transmission|communication]] across a [[chemical synapse]] occurs in a presynaptic to postsynaptic direction. It is used most commonly by those who argue that presynaptic neurons contribute significantly to the expression of LTP.<ref>{{cite book |last=Matthies|first=H.|chapter=Long-Term Synaptic Potentiation and Macromolecular Changes in Memory Formation|date=1988 | doi = 10.1007/978-3-642-73202-7_35|title=Synaptic Plasticity in the Hippocampus|pages=119–121|publisher=Springer Berlin Heidelberg|isbn=9783642732041}}</ref>

====Background====
Long-term potentiation is the persistent increase in the strength of a [[chemical synapse]] that lasts from hours to days.<ref name="Warburton_2015">{{cite book | vauthors = Warburton EC | chapter = Long-Term Potentiation and Memory | title = Encyclopedia of Psychopharmacology | date = 2015 | pages = 928–32 | doi = 10.1007/978-3-642-27772-6_345-2 | isbn = 978-3-642-27772-6 }}</ref> It is thought to occur via two temporally separated events, with ''induction'' occurring first, followed by ''expression''.<ref name="Warburton_2015" /> Most LTP investigators agree that induction is entirely postsynaptic, whereas there is disagreement as to whether expression is principally a presynaptic or postsynaptic event.<ref name="Nicoll_1995" /> Some researchers believe that both presynaptic and postsynaptic mechanisms play a role in LTP expression.<ref name="Nicoll_1995" />

Were LTP entirely induced and expressed postsynaptically, there would be no need for the postsynaptic cell to communicate with the presynaptic cell following LTP induction. However, postsynaptic induction combined with ''presynaptic'' expression requires that, following induction, the postsynaptic cell must communicate with the presynaptic cell. Because normal [[synaptic transmission]] occurs in a presynaptic to postsynaptic direction, postsynaptic to presynaptic communication is considered a form of ''retrograde'' transmission.<ref name="Regehr_2009" />

====Mechanism====
The retrograde signaling hypothesis proposes that during the early stages of LTP expression, the postsynaptic cell "sends a message" to the presynaptic cell to notify it that an LTP-inducing stimulus has been received postsynaptically. The general hypothesis of retrograde signaling does not propose a precise mechanism by which this message is sent and received. One mechanism may be that the postsynaptic cell synthesizes and releases a retrograde messenger upon receipt of LTP-inducing stimulation.<ref name="Garthwaite 1991">{{cite journal | vauthors = Garthwaite J | title = Glutamate, nitric oxide and cell-cell signalling in the nervous system | journal = Trends in Neurosciences | volume = 14 | issue = 2 | pages = 60–7 | date = February 1991 | pmid = 1708538 | doi = 10.1016/0166-2236(91)90022-M | s2cid = 22628126 }}</ref><ref name="Lei 2000">{{cite journal | vauthors = Lei S, Jackson MF, Jia Z, Roder J, Bai D, Orser BA, MacDonald JF | title = Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG | journal = Nature Neuroscience | volume = 3 | issue = 6 | pages = 559–65 | date = June 2000 | pmid = 10816311 | doi = 10.1038/75729 | s2cid = 21783160 }}</ref> Another is that it releases a preformed retrograde messenger upon such activation. Yet another mechanism is that synapse-spanning proteins may be altered by LTP-inducing stimuli in the postsynaptic cell, and that changes in conformation of these proteins propagates this information across the synapse and to the presynaptic cell.<ref name="Malenka 2004">{{cite journal | vauthors = Malenka RC, Bear MF | title = LTP and LTD: an embarrassment of riches | journal = Neuron | volume = 44 | issue = 1 | pages = 5–21 | date = September 2004 | pmid = 15450156 | doi = 10.1016/j.neuron.2004.09.012 | s2cid = 79844 | doi-access = free }}</ref>

====Identity of the messenger====
Of these mechanisms, the retrograde messenger hypothesis has received the most attention. Among proponents of the model, there is disagreement over the identity of the retrograde messenger. A flurry of work in the early 1990s to demonstrate the existence of a retrograde messenger and to determine its identity generated a list of candidates including [[carbon monoxide]],<ref>{{cite journal | vauthors = Alkadhi KA, Al-Hijailan RS, Malik K, Hogan YH | title = Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion | journal = The Journal of Neuroscience | volume = 21 | issue = 10 | pages = 3515–20 | date = May 2001 | pmid = 11331380 | pmc = 6762490 | doi = 10.1523/JNEUROSCI.21-10-03515.2001 }}</ref> [[platelet-activating factor]],<ref>{{cite journal | vauthors = Kato K, Zorumski CF | title = Platelet-activating factor as a potential retrograde messenger | journal = Journal of Lipid Mediators and Cell Signalling | volume = 14 | issue = 1–3 | pages = 341–8 | date = September 1996 | pmid = 8906580 | doi = 10.1016/0929-7855(96)00543-3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kato K, Clark GD, Bazan NG, Zorumski CF | title = Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation | journal = Nature | volume = 367 | issue = 6459 | pages = 175–9 | date = January 1994 | pmid = 8114914 | doi = 10.1038/367175a0 | bibcode = 1994Natur.367..175K | s2cid = 4326359 }}</ref> [[arachidonic acid]],<ref name="Carta 2014">{{cite journal | vauthors = Carta M, Lanore F, Rebola N, Szabo Z, Da Silva SV, Lourenço J, Verraes A, Nadler A, Schultz C, Blanchet C, Mulle C | display-authors = 6 | title = Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels | journal = Neuron | volume = 81 | issue = 4 | pages = 787–99 | date = February 2014 | pmid = 24486086 | doi = 10.1016/j.neuron.2013.12.028 | doi-access = free }}</ref> and nitric oxide. Nitric oxide has received a great deal of attention in the past, but has recently been superseded by [[adhesion protein]]s that span the synaptic cleft to join the presynaptic and postsynaptic cells.<ref name="Malenka 2004"/> The [[endocannabinoids]] [[anandamide]] and/or [[2-AG]], acting through [[GPCR|G-protein coupled]] [[cannabinoid receptor]]s, may play an important role in retrograde signaling in LTP.<ref name="Alger 2002" /><ref name="Wilson 2001" />