Editing Brain-derived neurotrophic factor (section)

== Role in synaptic transmission ==

=== 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.

=== GABAergic signaling ===

One mechanism through which BDNF appears to maintain elevated levels of neuronal excitation is through preventing [[GABA]]ergic signaling activities.<ref name="Henneberger_2002">{{cite journal | vauthors = Henneberger C, Jüttner R, Rothe T, Grantyn R | title = Postsynaptic action of BDNF on GABAergic synaptic transmission in the superficial layers of the mouse superior colliculus | journal = Journal of Neurophysiology | volume = 88 | issue = 2 | pages = 595–603 | date = August 2002 | pmid = 12163512 | doi =  10.1152/jn.2002.88.2.595| s2cid = 9287511 }}</ref>  While glutamate is the brain's major excitatory neurotransmitter and phosphorylation normally activates receptors, [[GABA]] is the brain's primary inhibitory neurotransmitter and phosphorylation of [[GABAA receptor|GABA<sub>A</sub> receptor]]s tend to reduce their activity.{{Clarify|date=March 2019}} Blockading BDNF signaling with a tyrosine kinase inhibitor or a PKC inhibitor in wild type mice produced significant reductions in spontaneous [[action potential]] frequencies that were mediated by an increase in the amplitude of GABAergic [[Inhibitory postsynaptic potential|inhibitory postsynaptic currents]] (IPSC).<ref name="Henneberger_2002"/>  Similar effects could be obtained in BDNF knockout mice, but these effects were reversed by local application of BDNF.<ref name="Henneberger_2002"/> 
This suggests BDNF increases excitatory synaptic signaling partly through the post-synaptic suppression of GABAergic signaling by activating PKC through its association with TrkB.<ref name="Henneberger_2002"/>  Once activated, PKC can reduce the amplitude of IPSCs through to GABAA receptor phosphorylation and inhibition.<ref name="Henneberger_2002"/>  In support of this putative mechanism, activation of PKCε leads to phosphorylation of N-ethylmaleimide-sensitive factor (NSF) at serine 460 and threonine 461, increasing its ATPase activity which downregulates GABAA receptor surface expression and subsequently attenuates inhibitory currents.<ref name="pmid20962217">{{cite journal | vauthors = Chou WH, Wang D, McMahon T, Qi ZH, Song M, Zhang C, Shokat KM, Messing RO | title = GABAA receptor trafficking is regulated by protein kinase C(epsilon) and the N-ethylmaleimide-sensitive factor | journal = The Journal of Neuroscience | volume = 30 | issue = 42 | pages = 13955–65 | date = October 2010 | pmid = 20962217 | pmc = 2994917 | doi = 10.1523/JNEUROSCI.0270-10.2010 }}</ref>

=== Synaptogenesis ===

BDNF also enhances synaptogenesis. [[Synaptogenesis]] is dependent upon the assembly of new synapses and the disassembly of old synapses by [[ADD2|β-adducin]].<ref name="Bednarek_2011">{{cite journal | vauthors = Bednarek E, Caroni P | title = β-Adducin is required for stable assembly of new synapses and improved memory upon environmental enrichment | journal = Neuron | volume = 69 | issue = 6 | pages = 1132–46 | date = March 2011 | pmid = 21435558 | doi = 10.1016/j.neuron.2011.02.034 | s2cid = 15373477 | doi-access = free }}</ref> Adducins are membrane-skeletal proteins that cap the growing ends of [[actin]] filaments and promote their association with spectrin, another cytoskeletal protein, to create stable and integrated cytoskeletal networks.<ref name="Matsuoka_2000">{{cite journal | vauthors = Matsuoka Y, Li X, Bennett V | title = Adducin: structure, function and regulation | journal = Cellular and Molecular Life Sciences | volume = 57 | issue = 6 | pages = 884–95 | date = June 2000 | pmid = 10950304 | doi = 10.1007/pl00000731 | s2cid = 29317393 | pmc = 11146971 }}</ref>  Actins have a variety of roles in synaptic functioning.  In pre-synaptic neurons, actins are involved in synaptic vesicle recruitment and vesicle recovery following neurotransmitter release.<ref name="Stevens_2011">{{cite journal | vauthors = Stevens RJ, Littleton JT | title = Synaptic growth: dancing with adducin | journal = Current Biology | volume = 21 | issue = 10 | pages = R402–5 | date = May 2011 | pmid = 21601803 | doi = 10.1016/j.cub.2011.04.020 | bibcode = 2011CBio...21.R402S | hdl = 1721.1/92025 | s2cid = 3182599 | hdl-access = free }}</ref>  In post-synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal.<ref name="Stevens_2011"/> At their C-terminus, adducins possess a myristoylated alanine-rich C kinase substrate (MARCKS) domain which regulates their capping activity.<ref name="Matsuoka_2000"/>  BDNF can reduce capping activities by upregulating PKC, which can bind to the adducing MRCKS domain, inhibit capping activity, and promote synaptogenesis through dendritic spine growth and disassembly and other activities.<ref name="Bednarek_2011"/><ref name="Stevens_2011"/>

=== Dendritogenesis ===

Local interaction of BDNF with the TrkB receptor on a single dendritic segment is able to stimulate an increase in PSD-95 trafficking to other separate dendrites as well as to the synapses of locally stimulated neurons.<ref name="pmid17515902">{{cite journal | vauthors = Yoshii A, Constantine-Paton M | title = BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation | journal = Nature Neuroscience | volume = 10 | issue = 6 | pages = 702–11 | date = June 2007 | pmid = 17515902 | doi = 10.1038/nn1903 | s2cid = 6486137 }}</ref> [[PSD-95]] localizes the actin-remodeling GTPases, [[Rac (GTPase)|Rac]] and [[Rho family of GTPases|Rho]], to synapses through the binding of its PDZ domain to [[kalirin]], increasing the number and size of spines.<ref name="pmid11182094">{{cite journal | vauthors = Penzes P, Johnson RC, Sattler R, Zhang X, Huganir RL, Kambampati V, Mains RE, Eipper BA | title = The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis | journal = Neuron | volume = 29 | issue = 1 | pages = 229–42 | date = January 2001 | pmid = 11182094 | doi = 10.1016/s0896-6273(01)00193-3 | s2cid = 7014018 | doi-access = free }}</ref> Thus, BDNF-induced trafficking of [[PSD-95]] to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF.