Editing Retrograde signaling (section)

==In neuroscience==
[[File:General Feedback Loop.svg|thumb|Feedback loop found in retrograde neurological signaling. ]]
The primary purpose of retrograde neurotransmission is regulation of chemical [[neurotransmission]].<ref name="Regehr 2009" /> For this reason, retrograde neurotransmission allows [[biological neural network|neural circuit]]s to create [[feedback loop]]s. In the sense that retrograde neurotransmission mainly serves to regulate typical, anterograde neurotransmission, rather than to actually distribute any information, it is similar to [[electrical synapse|electrical neurotransmission]].

In contrast to conventional (anterograde) neurotransmitters, retrograde neurotransmitters are synthesized in the postsynaptic neuron, and bind to receptors on the [[axon terminal]] of the presynaptic neuron.<ref>{{Cite journal|last1=Tao|first1=Huizhong W.|last2=Poo|first2=Mu-ming|date=2001-09-25|title=Retrograde signaling at central synapses|journal=Proceedings of the National Academy of Sciences|language=en|volume=98|issue=20|pages=11009–11015|doi=10.1073/pnas.191351698|issn=0027-8424|pmid=11572961|pmc=58675|bibcode=2001PNAS...9811009T|doi-access=free}}</ref> Additionally, retrograde signaling initiates a signaling cascade that focuses on the presynaptic neuron. Once retrograde signaling is initiated, there is an increase in action potentials that begin in the presynaptic neuron, which directly impacts the postsynaptic neuron by increasing the number of its receptors.<ref name=":0">{{Cite web|title=Endocannabinoids Performance through Retrograde Signaling {{!}} Cannabis Sciences|url=https://www.labroots.com/trending/cannabis-sciences/8519/endocannabinoids-performance-retrograde-signaling|access-date=2021-05-05|website=Labroots}}</ref>

[[Endocannabinoid]]s like [[anandamide]] are known to act as retrograde messengers,<ref name="Alger 2002">{{cite journal | vauthors = Alger BE | title = Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids | journal = Progress in Neurobiology | volume = 68 | issue = 4 | pages = 247–86 | date = November 2002 | pmid = 12498988 | doi = 10.1016/S0301-0082(02)00080-1 | s2cid = 22754679 }}</ref><ref name="Wilson 2001">{{cite journal | vauthors = Wilson RI, Nicoll RA | title = Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses | journal = Nature | volume = 410 | issue = 6828 | pages = 588–92 | date = March 2001 | pmid = 11279497 | doi = 10.1038/35069076 | bibcode = 2001Natur.410..588W | s2cid = 52803281 }}</ref><ref>{{cite journal | vauthors = Kreitzer AC, Regehr WG | title = Retrograde signaling by endocannabinoids | journal = Current Opinion in Neurobiology | volume = 12 | issue = 3 | pages = 324–30 | date = June 2002 | pmid = 12049940 | doi = 10.1016/S0959-4388(02)00328-8 | s2cid = 5846728 }}</ref> as is nitric oxide.<ref name="O'Dell 1991">{{cite journal | vauthors = O'Dell TJ, Hawkins RD, Kandel ER, Arancio O | title = Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 24 | pages = 11285–9 | date = December 1991 | pmid = 1684863 | pmc = 53119 | doi = 10.1073/pnas.88.24.11285 | bibcode = 1991PNAS...8811285O | doi-access = free }}</ref><ref name="Malen 1997">{{cite journal | vauthors = Malen PL, Chapman PF | title = Nitric oxide facilitates long-term potentiation, but not long-term depression | journal = The Journal of Neuroscience | volume = 17 | issue = 7 | pages = 2645–51 | date = April 1997 | pmid = 9065524 | pmc = 6573517 | doi = 10.1523/JNEUROSCI.17-07-02645.1997 }}</ref>

Retrograde signaling may also play a role in [[long-term potentiation]] (LTP), a proposed mechanism of learning and memory, although this is controversial.<ref name="Regehr_2009">{{cite journal | vauthors = Regehr WG, Carey MR, Best AR | title = Activity-dependent regulation of synapses by retrograde messengers | journal = Neuron | volume = 63 | issue = 2 | pages = 154–70 | date = July 2009 | pmid = 19640475 | doi = 10.1016/j.neuron.2009.06.021 | pmc = 3251517 }}</ref><ref name="Nicoll_1995">{{cite journal | vauthors = Nicoll RA, Malenka RC | title = Contrasting properties of two forms of long-term potentiation in the hippocampus | journal = Nature | volume = 377 | issue = 6545 | pages = 115–8 | date = September 1995 | pmid = 7675078 | doi = 10.1038/377115a0 | bibcode = 1995Natur.377..115N | s2cid = 4311817 }}</ref><ref>{{cite journal | vauthors = Abraham WC, Jones OD, Glanzman DL | title = Is plasticity of synapses the mechanism of long-term memory storage? | journal = npj Science of Learning | volume = 4 | issue = 1 | pages = 9 | date = December 2019 | pmid = 31285847 | pmc = 6606636 | doi = 10.1038/s41539-019-0048-y | bibcode = 2019npjSL...4....9A }}</ref>

===Formal definition of a retrograde neurotransmitter===
In 2009, Regehr ''et al.'' proposed criteria for defining retrograde neurotransmitters. According to their work, a signaling molecule can be considered a retrograde neurotransmitter if it satisfies all of the following criteria:<ref name="Regehr 2009" />

*The appropriate machinery for synthesizing and releasing the retrograde messenger must be located in the postsynaptic neuron
*Disrupting the synthesis and/or release of the messenger from the postsynaptic neuron must prevent retrograde signaling
*The appropriate targets for the retrograde messenger must be located in the presynaptic bouton
*Disrupting the targets for the retrograde messenger in the presynaptic boutons must eliminate retrograde signaling
*Exposing the presynaptic bouton to the messenger should mimic retrograde signaling provided the presence of the retrograde messenger is sufficient for retrograde signaling to occur
*In cases where the retrograde messenger is not sufficient, pairing the other factors with the retrograde signal should mimic the phenomenon

===Types of retrograde neurotransmitters===
The most prevalent endogenous retrograde neurotransmitters are [[nitric oxide]]<ref name="O'Dell 1991" /><ref name="Malen 1997" /> and various [[cannabinoid|endocannabinoid]]s, which are lipophilic ligands.<ref name=":0" /><ref>{{Cite book|last1=Vaughan|first1=C. W.|last2=Christie|first2=M. J.|date=2005|title=Retrograde signalling by endocannabinoids|series=Handbook of Experimental Pharmacology|volume=168|issue=168|pages=367–383|doi=10.1007/3-540-26573-2_12|issn=0171-2004|pmid=16596781|isbn=3-540-22565-X}}</ref>

The retrograde neurotransmitter, nitric oxide (NO) is a soluble gas that can readily diffuse through various cell membranes.<ref>{{Cite journal|last1=Arancio|first1=Ottavio|last2=Kiebler|first2=Michael|last3=Lee|first3=C. Justin|last4=Lev-Ram|first4=Varda|last5=Tsien|first5=Roger Y.|last6=Kandel|first6=Eric R.|last7=Hawkins|first7=Robert D.|date=1996-12-13|title=Nitric Oxide Acts Directly in the Presynaptic Neuron to Produce Long-Term Potentiationin Cultured Hippocampal Neurons|journal=Cell|language=English|volume=87|issue=6|pages=1025–1035|doi=10.1016/S0092-8674(00)81797-3|pmid=8978607|s2cid=10550701|issn=0092-8674|doi-access=free}}</ref> Nitric oxide synthase is the enzyme responsible for the synthesis of NO in various presynaptic cells.<ref>{{Cite journal|last1=Overeem|first1=Kathie A.|last2=Ota|first2=Kristie T.|last3=Monsey|first3=Melissa S.|last4=Ploski|first4=Jonathan E.|last5=Schafe|first5=Glenn E.|date=2010-02-05|title=A Role for Nitric Oxide-Driven Retrograde Signaling in the Consolidation of a Fear Memory|journal=Frontiers in Behavioral Neuroscience|volume=4|page=2|doi=10.3389/neuro.08.002.2010|issn=1662-5153|pmc=2820379|pmid=20161806|doi-access=free}}</ref> Specifically, NO is known to play a critical role in LTP, which plays an important role in memory storage within the hippocampus.<ref>{{Cite web|title=Long-Term Potentiation - an overview {{!}} ScienceDirect Topics|url=https://www.sciencedirect.com/topics/neuroscience/long-term-potentiation|access-date=2021-05-05|website=www.sciencedirect.com}}</ref> Additionally, literature suggests that NO can act as intracellular messengers in the brain and can also have an effect on the presynaptic glutamatergic and GABAergic synapses.<ref>{{Cite journal|last1=Hardingham|first1=Neil|last2=Dachtler|first2=James|last3=Fox|first3=Kevin|date=2013|title=The role of nitric oxide in pre-synaptic plasticity and homeostasis|journal=Frontiers in Cellular Neuroscience|language=English|volume=7|page=190|doi=10.3389/fncel.2013.00190|pmid=24198758|pmc=3813972|issn=1662-5102|doi-access=free}}</ref>

Utilizing retrograde signaling, endocannabinoids, a type of retrograde neurotransmitter, are activated when they bind to G-protein coupled receptors on the presynaptic terminals of neurons.<ref name=":1">{{Cite journal|date=2002-06-01|title=Retrograde signaling by endocannabinoids|url=https://www.sciencedirect.com/science/article/abs/pii/S0959438802003288|journal=Current Opinion in Neurobiology|language=en|volume=12|issue=3|pages=324–330|doi=10.1016/S0959-4388(02)00328-8|issn=0959-4388|last1=Kreitzer|first1=A.|last2=Regehr|first2=W. G.|pmid=12049940|s2cid=5846728|url-access=subscription}}</ref> The activation of endocannabinoids results in the release of particular neurotransmitters at the excitatory and inhibitory synapses of a neuron, ultimately impacting various forms of plasticity.<ref>{{Cite journal|date=2012-10-04|title=Endocannabinoid Signaling and Synaptic Function|journal=Neuron|language=en|volume=76|issue=1|pages=70–81|doi=10.1016/j.neuron.2012.09.020|issn=0896-6273|doi-access=free|last1=Castillo|first1=Pablo E.|last2=Younts|first2=Thomas J.|last3=Chávez|first3=Andrés E.|last4=Hashimotodani|first4=Yuki|pmid=23040807|pmc=3517813}}</ref><ref name=":0" /><ref name=":1" />

===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" />