Editing Brain-derived neurotrophic factor (section)

=== Glutamatergic signaling ===

[[Glutamate (neurotransmitter)|Glutamate]] is the brain's major excitatory [[neurotransmitter]] and its release can trigger the [[depolarization]] of [[postsynaptic]] neurons. [[AMPA]] and [[NMDA]] receptors are two [[ionotropic receptor|ionotropic]] glutamate receptors involved in [[Glutamic acid#Neurotransmitter|glutamatergic neurotransmission]] and essential to learning and memory via [[long-term potentiation]].  While [[AMPA receptor]] activation leads to depolarization via sodium influx, [[NMDA receptor]] activation by rapid successive firing allows calcium influx in addition to sodium.  The calcium influx triggered through NMDA receptors can lead to expression of BDNF, as well as other genes thought to be involved in LTP, [[Dendrite|dendritogenesis]], and synaptic stabilization.

==== NMDA receptor activity ====

NMDA receptor activation is essential to producing the activity-dependent molecular changes involved in the formation of new memories.  Following exposure to an enriched environment, BDNF and NR1 phosphorylation levels are upregulated simultaneously, probably because BDNF is capable of phosphorylating NR1 subunits, in addition to its many other effects.<ref name="Slack_2004">{{cite journal | vauthors = Slack SE, Pezet S, McMahon SB, Thompson SW, Malcangio M | title = Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord | journal = The European Journal of Neuroscience | volume = 20 | issue = 7 | pages = 1769–78 | date = October 2004 | pmid = 15379998 | doi = 10.1111/j.1460-9568.2004.03656.x | s2cid = 23108942 }}</ref><ref name="Xu_2009">{{cite journal | vauthors = Xu X, Ye L, Ruan Q | title = Environmental enrichment induces synaptic structural modification after transient focal cerebral ischemia in rats | journal = Experimental Biology and Medicine | volume = 234 | issue = 3 | pages = 296–305 | date = March 2009 | pmid = 19244205 | doi = 10.3181/0804-RM-128 | s2cid = 39825785 }}</ref> One of the primary ways BDNF can modulate NMDA receptor activity is through phosphorylation and activation of the NMDA receptor one subunit, particularly at the PKC Ser-897 site.<ref name="Slack_2004"/> The mechanism underlying this activity is dependent upon both [[Extracellular signal-regulated kinases|ERK]] and [[Protein kinase C|PKC]] signaling pathways, each acting individually, and all NR1 phosphorylation activity is lost if the TrKB receptor is blocked.<ref name="Slack_2004"/> PI3 kinase and Akt are also essential in BDNF-induced potentiation of NMDA receptor function and inhibition of either molecule eliminated receptor BDNF can also increase NMDA receptor activity through phosphorylation of the [[NR2B]] subunit.  BDNF signaling leads to the autophosphorylation of the intracellular domain of the TrkB receptor (ICD-TrkB).  Upon autophosphorylation, [[FYN|Fyn]] associates with the pICD-TrkB through its [[SH2 domain|Src homology domain 2]] (SH2) and is phosphorylated at its Y416 site.<ref name="pmid20368433">{{cite journal | vauthors = Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T | title = Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 16 | pages = 7586–91 | date = April 2010 | pmid = 20368433 | pmc = 2867726 | doi = 10.1073/pnas.0914514107 | bibcode = 2010PNAS..107.7586N | doi-access = free }}</ref><ref name="pmid9648856">{{cite journal | vauthors = Iwasaki Y, Gay B, Wada K, Koizumi S | title = Association of the Src family tyrosine kinase Fyn with TrkB | journal = Journal of Neurochemistry | volume = 71 | issue = 1 | pages = 106–11 | date = July 1998 | pmid = 9648856 | doi = 10.1046/j.1471-4159.1998.71010106.x | s2cid = 9012343 }}</ref> Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr-1472 site.<ref name="pmid11024032">{{cite journal | vauthors = Nakazawa T, Komai S, Tezuka T, Hisatsune C, Umemori H, Semba K, Mishina M, Manabe T, Yamamoto T | title = Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor | journal = The Journal of Biological Chemistry | volume = 276 | issue = 1 | pages = 693–99 | date = January 2001 | pmid = 11024032 | doi = 10.1074/jbc.M008085200 | doi-access = free }}</ref>  Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus.<ref name="pmid12663749">{{cite journal | vauthors = Mizuno M, Yamada K, He J, Nakajima A, Nabeshima T | title = Involvement of BDNF receptor TrkB in spatial memory formation | journal = Learning & Memory | volume = 10 | issue = 2 | pages = 108–15 | year = 2003 | pmid = 12663749 | pmc = 196664 | doi = 10.1101/lm.56003 }}</ref><ref name="pmid9892651">{{cite journal | vauthors = Tezuka T, Umemori H, Akiyama T, Nakanishi S, Yamamoto T | title = PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 2 | pages = 435–40 | date = January 1999 | pmid = 9892651 | pmc = 15154 | doi = 10.1073/pnas.96.2.435 | bibcode = 1999PNAS...96..435T | doi-access = free }}</ref> Thus, BDNF can increase NMDA receptor activity through Fyn activation.  This has been shown to be important for processes such as spatial memory in the hippocampus, demonstrating the therapeutic and functional relevance of BDNF-mediated NMDA receptor activation.<ref name="pmid12663749"/>

==== Synapse stability ====

In addition to mediating transient effects on NMDAR activation to promote memory-related molecular changes, BDNF should also initiate more stable effects that could be maintained in its absence and not depend on its expression for long term synaptic support.<ref name="pmid14706865">{{cite journal | vauthors = Briones TL, Suh E, Jozsa L, Hattar H, Chai J, Wadowska M | title = Behaviorally-induced ultrastructural plasticity in the hippocampal region after cerebral ischemia | journal = Brain Research | volume = 997 | issue = 2 | pages = 137–46 | date = February 2004 | pmid = 14706865 | doi = 10.1016/j.brainres.2003.10.030 | s2cid = 34763792 }}</ref>
It was previously mentioned that [[AMPA]] receptor expression is essential to learning and memory formation, as these are the components of the synapse that will communicate regularly and maintain the synapse structure and function long after the initial activation of NMDA channels.  BDNF is capable of increasing the mRNA expression of GluR1 and GluR2 through its interaction with the TrkB receptor and promoting the synaptic localization of [[GluR1]] via PKC- and CaMKII-mediated Ser-831 phosphorylation.<ref name="pmid17337442">{{cite journal | vauthors = Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS, Backos DS, Carvalho AL, Esteban JA, Duarte CB | title = Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons | journal = The Journal of Biological Chemistry | volume = 282 | issue = 17 | pages = 12619–28 | date = April 2007 | pmid = 17337442 | doi = 10.1074/jbc.M700607200 | doi-access = free }}</ref>  It also appears that BDNF is able to influence [[Gl1]] activity through its effects on NMDA receptor activity.<ref name="Wu_2004">{{cite journal | vauthors = Wu K, Len GW, McAuliffe G, Ma C, Tai JP, Xu F, Black IB | title = Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms | journal = Brain Research. Molecular Brain Research | volume = 130 | issue = 1–2 | pages = 178–86 | date = November 2004 | pmid = 15519688 | doi = 10.1016/j.molbrainres.2004.07.019 }}</ref>  BDNF significantly enhanced the activation of GluR1 through phosphorylation of tyrosine830, an effect that was abolished in either the presence of a specific [[NR2B]] antagonist or a trk receptor tyrosine kinase inhibitor.<ref name="Wu_2004"/> Thus, it appears BDNF can upregulate the expression and synaptic localization of AMPA receptors, as well as enhance their activity through its postsynaptic interactions with the NR2B subunit. Further, BDNF can regulate the nanoscale architecture of adhesion proteins such as [[Neogenin]] which are essential for spine enlargement and activity.<ref name="pmid39228790">{{cite journal | vauthors = Shohayeb B, Sempert K, Wallis TP, Meunier FA, Durisic N, O'Brien EA, Flores C, Cooper HM | title = BDNF-dependent nano-organization of Neogenin and the WAVE regulatory complex promotes actin remodeling in dendritic spines | journal = iScience | volume = 27 | issue = 9 | pages = 2589-0042 | date = September 2024 | pmid = 39228790| doi = 10.1016/j.isci.2024.110621 | pmc = 11369513 }}</ref> This suggests BDNF is not only capable of initiating synapse formation through its effects on NMDA receptor activity, but it can also support the regular every-day signaling necessary for stable memory function.