Brain-derived neurotrophic factor#expression

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system expressing TrkB, helping to support survival of existing neurons, and encouraging growth and differentiation of new neurons and synapses.{{cite journal | vauthors = Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM | title = A BDNF autocrine loop in adult sensory neurons prevents cell death | journal = Nature | volume = 374 | issue = 6521 | pages = 450–53 | date = March 1995 | pmid = 7700353 | doi = 10.1038/374450a0 | bibcode = 1995Natur.374..450A | s2cid = 4316241 }}{{cite journal | vauthors = Huang EJ, Reichardt LF | title = Neurotrophins: roles in neuronal development and function | journal = Annual Review of Neuroscience | volume = 24 | pages = 677–736 | year = 2001 | pmid = 11520916 | pmc = 2758233 | doi = 10.1146/annurev.neuro.24.1.677 }} In the brain it is active in the hippocampus, cortex, and basal forebrain {{Ndash}}areas vital to learning, memory, and higher thinking.{{cite journal | vauthors = Yamada K, Nabeshima T | title = Brain-derived neurotrophic factor/TrkB signaling in memory processes | journal = Journal of Pharmacological Sciences | volume = 91 | issue = 4 | pages = 267–70 | date = April 2003 | pmid = 12719654 | doi = 10.1254/jphs.91.267 | doi-access = free }} BDNF is also expressed in the retina, kidneys, prostate, motor neurons, and skeletal muscle, and is also found in saliva.{{cite journal | vauthors = Mandel AL, Ozdener H, Utermohlen V | title = Identification of pro- and mature brain-derived neurotrophic factor in human saliva | journal = Archives of Oral Biology | volume = 54 | issue = 7 | pages = 689–95 | date = July 2009 | pmid = 19467646 | pmc = 2716651 | doi = 10.1016/j.archoralbio.2009.04.005 }}{{cite journal | vauthors = Delezie J, Handschin C | title = Endocrine Crosstalk Between Skeletal Muscle and the Brain | journal = Frontiers in Neurology | volume = 9 | pages = 698 | year = 2018 | pmid = 30197620 | pmc = 6117390 | doi = 10.3389/fneur.2018.00698 | doi-access = free }}

BDNF itself is important for long-term memory.{{cite journal | vauthors = Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH | title = BDNF is essential to promote persistence of long-term memory storage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 7 | pages = 2711–16 | date = February 2008 | pmid = 18263738 | pmc = 2268201 | doi = 10.1073/pnas.0711863105 | bibcode = 2008PNAS..105.2711B | doi-access = free }}

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active.{{cite journal | vauthors = Zigova T, Pencea V, Wiegand SJ, Luskin MB | title = Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb | journal = Molecular and Cellular Neurosciences | volume = 11 | issue = 4 | pages = 234–45 | date = July 1998 | pmid = 9675054 | doi = 10.1006/mcne.1998.0684 | s2cid = 35630924 }}{{cite journal | vauthors = Benraiss A, Chmielnicki E, Lerner K, Roh D, Goldman SA | title = Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain | journal = The Journal of Neuroscience | volume = 21 | issue = 17 | pages = 6718–31 | date = September 2001 | pmid = 11517261 | pmc = 6763117 | doi = 10.1523/JNEUROSCI.21-17-06718.2001 }}{{cite journal | vauthors = Pencea V, Bingaman KD, Wiegand SJ, Luskin MB | title = Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus | journal = The Journal of Neuroscience | volume = 21 | issue = 17 | pages = 6706–17 | date = September 2001 | pmid = 11517260 | pmc = 6763082 | doi = 10.1523/JNEUROSCI.21-17-06706.2001 }} Mice born without the ability to make BDNF have developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.{{cite journal | vauthors = Ernfors P, Kucera J, Lee KF, Loring J, Jaenisch R | title = Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice | journal = The International Journal of Developmental Biology | volume = 39 | issue = 5 | pages = 799–807 | date = October 1995 | pmid = 8645564 | url = http://www.intjdevbiol.com/paper.php?doi=8645564 }} Other important neurotrophins structurally related to BDNF include NT-3, NT-4, and NGF.

BDNF is made in the endoplasmic reticulum and secreted from dense-core vesicles. It binds carboxypeptidase E (CPE), and disruption of this binding has been proposed to cause the loss of sorting BDNF into dense-core vesicles. The phenotype for BDNF knockout mice can be severe, including postnatal lethality. Other traits include sensory neuron losses that affect coordination, balance, hearing, taste, and breathing. Knockout mice also exhibit cerebellar abnormalities and an increase in the number of sympathetic neurons.MGI database: phenotypes for BDNF homozygous null mice. http://www.informatics.jax.org/searches/allele_report.cgi?_Marker_key=537&int:_Set_key=847156

Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise-induced neurogenesis and improvements in cognitive function.{{cite journal | vauthors = Szuhany KL, Bugatti M, Otto MW | title = A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor | journal = Journal of Psychiatric Research | volume = 60 | pages = 56–64 | date = January 2015 | pmid = 25455510 | pmc = 4314337 | doi = 10.1016/j.jpsychires.2014.10.003 }}{{cite journal | vauthors = Denham J, Marques FZ, O'Brien BJ, Charchar FJ | title = Exercise: putting action into our epigenome | journal = Sports Medicine | volume = 44 | issue = 2 | pages = 189–209 | date = February 2014 | pmid = 24163284 | doi = 10.1007/s40279-013-0114-1 | s2cid = 30210091 }}{{cite journal | vauthors = Phillips C, Baktir MA, Srivatsan M, Salehi A | title = Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 170 | year = 2014 | pmid = 24999318 | pmc = 4064707 | doi = 10.3389/fncel.2014.00170 | doi-access = free }}{{cite journal | vauthors = Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J | title = Organ-specific physiological responses to acute physical exercise and long-term training in humans | journal = Physiology | volume = 29 | issue = 6 | pages = 421–36 | date = November 2014 | pmid = 25362636 | doi = 10.1152/physiol.00067.2013 }} Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well.{{cite journal | vauthors = Fu L, Doreswamy V, Prakash R | title = The biochemical pathways of central nervous system neural degeneration in niacin deficiency | journal = Neural Regeneration Research | volume = 9 | issue = 16 | pages = 1509–13 | date = August 2014 | pmid = 25317166 | pmc = 4192966 | doi = 10.4103/1673-5374.139475 | doi-access = free }}

BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkB (pronounced "Track B") and the LNGFR (for low-affinity nerve growth factor receptor, also known as p75).{{cite journal | vauthors = Patapoutian A, Reichardt LF | title = Trk receptors: mediators of neurotrophin action | journal = Current Opinion in Neurobiology | volume = 11 | issue = 3 | pages = 272–80 | date = June 2001 | pmid = 11399424 | doi = 10.1016/S0959-4388(00)00208-7 | s2cid = 8000523 }} It may also modulate the activity of various neurotransmitter receptors, including the Alpha-7 nicotinic receptor.{{cite journal | vauthors = Fernandes CC, Pinto-Duarte A, Ribeiro JA, Sebastião AM | title = Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated responses in hippocampal interneurons | journal = The Journal of Neuroscience | volume = 28 | issue = 21 | pages = 5611–18 | date = May 2008 | pmid = 18495895 | pmc = 6670615 | doi = 10.1523/JNEUROSCI.5378-07.2008 }} BDNF has also been shown to interact with the reelin signaling chain.{{cite journal | author = Fatemi, S. Hossein | title = Reelin glycoprotein: Structure, biology and roles in health and disease | date = 2005 | journal = Molecular Psychiatry | volume = 10 | issue = 3 | publisher = Springer | location = Berlin | pages = 251–7 | isbn = 978-0-387-76760-4 | doi = 10.1038/sj.mp.4001613| pmid = 15583703 | s2cid = 21206951 }}; see the chapter "A Tale of Two Genes: Reelin and BDNF"; pp. 237–45 The expression of reelin by Cajal–Retzius cells goes down during development under the influence of BDNF.{{cite journal | vauthors = Ringstedt T, Linnarsson S, Wagner J, Lendahl U, Kokaia Z, Arenas E, Ernfors P, Ibáñez CF | title = BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex | journal = Neuron | volume = 21 | issue = 2 | pages = 305–15 | date = August 1998 | pmid = 9728912 | doi = 10.1016/S0896-6273(00)80540-1 | s2cid = 13983709 | doi-access = free }} The latter also decreases reelin expression in neuronal culture.

The TrkB receptor is encoded by the NTRK2 gene and is member of a receptor family of tyrosine kinases that includes TrkA and TrkC. TrkB autophosphorylation is dependent upon its ligand-specific association with BDNF, a widely expressed activity-dependent neurotrophic factor that regulates plasticity and is dysregulated following hypoxic injury. The activation of the BDNF-TrkB pathway is important in the development of short-term memory and the growth of neurons.{{citation needed|date=January 2016}}

The role of the other BDNF receptor, p75, is less clear. While the TrkB receptor interacts with BDNF in a ligand-specific manner, all neurotrophins can interact with the p75 receptor.{{cite journal | vauthors = Bartkowska K, Paquin A, Gauthier AS, Kaplan DR, Miller FD | title = Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development | journal = Development | volume = 134 | issue = 24 | pages = 4369–80 | date = December 2007 | pmid = 18003743 | doi = 10.1242/dev.008227 | doi-access = free }} When the p75 receptor is activated, it leads to activation of NFkB receptor. Thus, neurotrophic signaling may trigger apoptosis rather than survival pathways in cells expressing the p75 receptor in the absence of Trk receptors. Recent studies have revealed a truncated isoform of the TrkB receptor (t-TrkB) may act as a dominant negative to the p75 neurotrophin receptor, inhibiting the activity of p75, and preventing BDNF-mediated cell death.{{cite journal | vauthors = Michaelsen K, Zagrebelsky M, Berndt-Huch J, Polack M, Buschler A, Sendtner M, Korte M | title = Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons | journal = The European Journal of Neuroscience | volume = 32 | issue = 11 | pages = 1854–65 | date = December 2010 | pmid = 20955473 | doi = 10.1111/j.1460-9568.2010.07460.x | s2cid = 23496332 }}

The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11. Structurally, BDNF transcription is controlled by eight different promoters, each leading to different transcripts containing one of eight untranslated 5' exons (I to VIII) spliced to the 3' encoding exon. Promoter IV activity, leading to the translation of exon IV-containing mRNA, is strongly stimulated by calcium and is primarily under the control of a Cre regulatory component, suggesting a putative role for the transcription factor CREB and the source of BDNF's activity-dependent effects .{{cite journal | vauthors = Zheng F, Wang H | title = NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially regulated in cultured cortical neurons | journal = Neurochemistry International | volume = 54 | issue = 5–6 | pages = 385–92 | year = 2009 | pmid = 19418634 | pmc = 2722960 | doi = 10.1016/j.neuint.2009.01.006 }}

There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression. Stimulus-mediated neuronal excitation can lead to NMDA receptor activation, triggering a calcium influx. Through a protein signaling cascade requiring Erk, CaM KII/IV, PI3K, and PLC, NMDA receptor activation is capable of triggering BDNF exon IV transcription. BDNF exon IV expression also seems capable of further stimulating its own expression through TrkB activation. BDNF is released from the post-synaptic membrane in an activity-dependent manner, allowing it to act on local TrkB receptors and mediate effects that can lead to signaling cascades also involving Erk and CaM KII/IV.{{cite journal | vauthors = Kuzumaki N, Ikegami D, Tamura R, Hareyama N, Imai S, Narita M, Torigoe K, Niikura K, Takeshima H, Ando T, Igarashi K, Kanno J, Ushijima T, Suzuki T, Narita M | title = Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment | journal = Hippocampus | volume = 21 | issue = 2 | pages = 127–32 | date = February 2011 | pmid = 20232397 | doi = 10.1002/hipo.20775 | s2cid = 205912003 | doi-access = free }} Both of these pathways probably involve calcium-mediated phosphorylation of CREB at Ser133, thus allowing it to interact with BDNF's Cre regulatory domain and upregulate transcription.{{cite journal | vauthors = Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME | title = Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism | journal = Neuron | volume = 20 | issue = 4 | pages = 709–26 | date = April 1998 | pmid = 9581763 | doi = 10.1016/s0896-6273(00)81010-7 | s2cid = 770523 | doi-access = free }} However, NMDA-mediated receptor signaling is probably necessary to trigger the upregulation of BDNF exon IV expression because normally CREB interaction with CRE and the subsequent translation of the BDNF transcript is blocked by of the basic helix–loop–helix transcription factor protein 2 (BHLHB2).{{cite journal | vauthors = Jiang X, Tian F, Du Y, Copeland NG, Jenkins NA, Tessarollo L, Wu X, Pan H, Hu XZ, Xu K, Kenney H, Egan SE, Turley H, Harris AL, Marini AM, Lipsky RH | title = BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability | journal = The Journal of Neuroscience | volume = 28 | issue = 5 | pages = 1118–30 | date = January 2008 | pmid = 18234890 | pmc = 6671398 | doi = 10.1523/JNEUROSCI.2262-07.2008 }} NMDA receptor activation triggers the release of the regulatory inhibitor, allowing for BDNF exon IV upregulation to take place in response to the activity-initiated calcium influx. Activation of dopamine receptor D₅ also promotes expression of BDNF in prefrontal cortex neurons.{{cite journal | vauthors = Perreault ML, Jones-Tabah J, O'Dowd BF, George SR | title = A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex | journal = The International Journal of Neuropsychopharmacology | volume = 16 | issue = 2 | pages = 477–83 | date = March 2013 | pmid = 22827965 | pmc = 3802523 | doi = 10.1017/S1461145712000685 }}

The genomic locus encoding BDNF is structurally complex and also encodes BDNF-antisense (BDNF-AS; also known as BDNFOS or ANTI-BDNF).{{cite journal | vauthors = Lipovich L, Dachet F, Cai J, Bagla S, Balan K, Jia H, Loeb JA | title = Activity-dependent human brain coding/noncoding gene regulatory networks | journal = Genetics | volume = 192 | issue = 3 | pages = 1133–1148 | date = November 2012 | pmid = 22960213 | pmc = 3522156 | doi = 10.1534/genetics.112.145128 | doi-access = free }}{{cite journal | vauthors = Shkundin A, Halaris A | title = Associations of BDNF/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder | journal = Journal of Personalized Medicine| volume = 13 | issue = 9 | pages = 1395 | date = September 18, 2023 | doi = 10.3390/jpm13091395 | pmc = 10533016 | pmid = 37763162 | doi-access = free }}{{cite journal | vauthors = Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T | title = Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters | journal = Genomics | volume = 90 | issue = 3 | pages = 397–406 | date = September 2007 | pmc = 2568880 | pmid = 17629449 | doi = 10.1016/j.ygeno.2007.05.004 | doi-access = free }} BDNF-AS is a long non-coding RNA (lncRNA) transcribed from the opposite strand of the BDNF gene. This lncRNA was identified in 2005 through searches in expressed sequence tag (EST) databases and subsequent RT-PCR experiments.{{cite journal | vauthors = Ghafouri-Fard S, Khoshbakht T, Taheri M, Ghanbari M | title = A concise review on the role of BDNF-AS in human disorders | journal = Biomedicine & Pharmacotherapy | volume = 142 | pages = 112051 | date = October 2021 | doi = 10.1016/j.biopha.2021.112051 | pmid = 34426254 | doi-access = free }}{{cite journal | vauthors = Liu QR, Walther D, Drgon T, Polesskaya O, Lesnick TG, Strain KJ, de Andrade M, Bower JH, Maraganore DM, Uhl GR | title = Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease | journal = American Journal of Medical Genetics | volume = 134B | issue = 1 | pages = 93–103 | date = April 5, 2005 | doi = 10.1002/ajmg.b.30109 | pmid = 15666411 }} The gene encoding BDNF-AS is located on chromosome 11p14.1. BDNF mRNA and BDNF-AS share a common overlapping region and form double-stranded RNA (dsRNA) duplexes.

BDNF-AS regulates BDNF expression and can suppress BDNF mRNA. In the human neocortex, regions with increased activity and BDNF expression exhibit reduced BDNF-AS expression. Elevated BDNF-AS levels are associated with reduced BDNF expression and have been shown to promote neurotoxicity, increase apoptosis, and decrease cell viability. Conversely, inhibiting BDNF-AS upregulates BDNF mRNA, activates BDNF-mediated signaling pathways, increases BDNF protein levels, suppresses neuronal apoptosis, and promotes neuronal outgrowth and differentiation.

The BDNF-AS gene consists of 10 exons and a functional promoter upstream of exon 1. The BDNF-AS gene generates numerous distinct non-coding RNAs through alternative splicing. This diversity of spliced isoforms is a common feature of eukaryotic organisms, particularly in the nervous system. Notably, BDNF-AS is absent in rodents, although highly homologous sequences are present in the genomes of chimpanzees and rhesus monkeys, suggesting a primate/hominid evolutionary origin of BDNF-AS.

Variations in both the BDNF and BDNF-AS genes are important factors to consider, given their potential to alter BDNF function and contribute to multiple human phenotypes influencing disease susceptibility and treatment outcomes.

BDNF has several known single nucleotide polymorphisms (SNP), including, but not limited to, rs6265, C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442. rs6265 is the most studied SNP in the BDNF gene.{{cite journal | vauthors = Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR | title = The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function | journal = Cell | volume = 112 | issue = 2 | pages = 257–69 | date = January 2003 | pmid = 12553913 | doi = 10.1016/S0092-8674(03)00035-7 | s2cid = 12748901 | doi-access = free }}{{cite journal | vauthors = Bath KG, Lee FS | title = Variant BDNF (Val66Met) impact on brain structure and function | journal = Cognitive, Affective, & Behavioral Neuroscience | volume = 6 | issue = 1 | pages = 79–85 | date = March 2006 | pmid = 16869232 | doi = 10.3758/CABN.6.1.79 | doi-access = free }}

A common SNP in the BDNF gene is rs6265.{{cite journal | vauthors = Baj G, Carlino D, Gardossi L, Tongiorgi E | title = Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking | journal = Frontiers in Neuroscience | volume = 7 | pages = 188 | date = October 2013 | pmid = 24198753 | doi = 10.3389/fnins.2013.00188 | pmc=3812868| doi-access = free }} This point mutation in the coding sequence, a guanine to adenine switch at position 196, results in an amino acid switch: valine to methionine exchange at codon 66, Val66Met, which is in the prodomain of BDNF. Val66Met is unique to humans.

The mutation interferes with normal translation and intracellular trafficking of BDNF mRNA, as it destabilizes the mRNA and renders it prone to degradation. The proteins resulting from mRNA that does get translated, are not trafficked and secreted normally, as the amino acid change occurs on the portion of the prodomain where sortilin binds; and sortilin is essential for normal trafficking.{{cite journal | vauthors = Cunha C, Brambilla R, Thomas KL | title = A simple role for BDNF in learning and memory? | journal = Frontiers in Molecular Neuroscience | volume = 3 | pages = 1 | date = 2010-01-01 | pmid = 20162032 | pmc = 2821174 | doi = 10.3389/neuro.02.001.2010 | doi-access = free }}

The Val66Met mutation results in a reduction of hippocampal tissue and has since been reported in a high number of individuals with learning and memory disorders, anxiety disorders,{{cite journal | vauthors = Dincheva I, Lynch NB, Lee FS | title = The Role of BDNF in the Development of Fear Learning | journal = Depression and Anxiety | volume = 33 | issue = 10 | pages = 907–916 | date = October 2016 | pmid = 27699937 | pmc = 5089164 | doi = 10.1002/da.22497 }} major depression,{{cite journal | vauthors = Youssef MM, Underwood MD, Huang YY, Hsiung SC, Liu Y, Simpson NR, Bakalian MJ, Rosoklija GB, Dwork AJ, Arango V, Mann JJ | title = Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide | journal = The International Journal of Neuropsychopharmacology | volume = 21 | issue = 6 | pages = 528–538 | date = June 2018 | pmid = 29432620 | pmc = 6007393 | doi = 10.1093/ijnp/pyy008 }} and neurodegenerative diseases such as Alzheimer's and Parkinson's.{{cite journal | vauthors = Lu B, Nagappan G, Guan X, Nathan PJ, Wren P | title = BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases | journal = Nature Reviews. Neuroscience | volume = 14 | issue = 6 | pages = 401–16 | date = June 2013 | pmid = 23674053 | doi = 10.1038/nrn3505 | s2cid = 2065483 }}

A meta-analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.{{cite journal | vauthors = Terracciano A, Piras MG, Lobina M, Mulas A, Meirelles O, Sutin AR, Chan W, Sanna S, Uda M, Crisponi L, Schlessinger D | title = Genetics of serum BDNF: meta-analysis of the Val66Met and genome-wide association study | journal = The World Journal of Biological Psychiatry | volume = 14 | issue = 8 | pages = 583–89 | date = December 2013 | pmid = 22047184 | pmc = 3288597 | doi = 10.3109/15622975.2011.616533 }}

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 glutamate receptors involved in 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, dendritogenesis, and synaptic stabilization.

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.{{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 }}{{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 }} 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. The mechanism underlying this activity is dependent upon both ERK and PKC signaling pathways, each acting individually, and all NR1 phosphorylation activity is lost if the TrKB receptor is blocked. 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 associates with the pICD-TrkB through its Src homology domain 2 (SH2) and is phosphorylated at its Y416 site.{{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 }}{{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 }} Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr-1472 site.{{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 }} Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus.{{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 }}{{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 }} 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.

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.{{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 }}

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.{{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 }} It also appears that BDNF is able to influence Gl1 activity through its effects on NMDA receptor activity.{{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 }} 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. 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.{{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 }} 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.

One mechanism through which BDNF appears to maintain elevated levels of neuronal excitation is through preventing GABAergic signaling activities.{{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 }} 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 GABA_A receptors 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 currents (IPSC). Similar effects could be obtained in BDNF knockout mice, but these effects were reversed by local application of BDNF.

This suggests BDNF increases excitatory synaptic signaling partly through the post-synaptic suppression of GABAergic signaling by activating PKC through its association with TrkB. Once activated, PKC can reduce the amplitude of IPSCs through to GABAA receptor phosphorylation and inhibition. 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.{{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 }}

BDNF also enhances synaptogenesis. Synaptogenesis is dependent upon the assembly of new synapses and the disassembly of old synapses by β-adducin.{{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 }} 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.{{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 }} 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.{{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 }} In post-synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal. At their C-terminus, adducins possess a myristoylated alanine-rich C kinase substrate (MARCKS) domain which regulates their capping activity. 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.

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.{{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 }} PSD-95 localizes the actin-remodeling GTPases, Rac and Rho, to synapses through the binding of its PDZ domain to kalirin, increasing the number and size of spines.{{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 }} Thus, BDNF-induced trafficking of PSD-95 to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF.

Laboratory studies indicate that BDNF may play a role in neurogenesis. BDNF can promote protective pathways and inhibit damaging pathways in the NSCs and NPCs that contribute to the brain's neurogenic response by enhancing cell survival. This becomes especially evident following suppression of TrkB activity. TrkB inhibition results in a 2–3 fold increase in cortical precursors displaying EGFP-positive condensed apoptotic nuclei and a 2–4 fold increase in cortical precursors that stained immunopositive for cleaved caspase-3. BDNF can also promote NSC and NPC proliferation through Akt activation and PTEN inactivation.{{cite journal | vauthors = Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM | title = PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway | journal = The Journal of Biological Chemistry | volume = 274 | issue = 29 | pages = 20693–703 | date = July 1999 | pmid = 10400703 | doi = 10.1074/jbc.274.29.20693 | doi-access = free }} Some studies suggest that BDNF may promote neuronal differentiation.{{cite journal | vauthors = Bath KG, Akins MR, Lee FS | title = BDNF control of adult SVZ neurogenesis | journal = Developmental Psychobiology | volume = 54 | issue = 6 | pages = 578–89 | date = September 2012 | pmid = 21432850 | pmc = 3139728 | doi = 10.1002/dev.20546 }}

Preliminary research has focused on the possible links between BDNF and clinical conditions, such as depression,{{cite journal | vauthors = Cavaleri D, Moretti F, Bartoccetti A, Mauro S, Crocamo C, Carrà G, Bartoli F | title = The role of BDNF in major depressive disorder, related clinical features, and antidepressant treatment: Insight from meta-analyses | language = English | journal = Neuroscience and Biobehavioral Reviews | volume = 149 | page = 105159 | date = April 2023 | pmid = 37019247 | doi = 10.1016/j.neubiorev.2023.105159 | s2cid = 257915698 | department = Review | doi-access = free | hdl = 10281/412775 | hdl-access = free }} schizophrenia,{{cite journal | vauthors = Xiu MH, Hui L, Dang YF, Hou TD, Zhang CX, Zheng YL, Chen DC, Kosten TR, Zhang XY | title = Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 33 | issue = 8 | pages = 1508–12 | date = November 2009 | pmid = 19720106 | doi = 10.1016/j.pnpbp.2009.08.011 | s2cid = 43300334 }} and Alzheimer's disease.{{cite journal | vauthors = Zuccato C, Cattaneo E | author-link2=Elena Cattaneo | title = Brain-derived neurotrophic factor in neurodegenerative diseases | journal = Nature Reviews. Neurology | volume = 5 | issue = 6 | pages = 311–22 | date = June 2009 | pmid = 19498435 | doi = 10.1038/nrneurol.2009.54 | s2cid=30782827 }}

{{See also|Epigenetics of schizophrenia#Methylation of BDNF}}

Preliminary studies have assessed a possible relationship between schizophrenia and BDNF.{{cite journal | vauthors = Xiong P, Zeng Y, Wu Q, Han Huang DX, Zainal H, Xu X, Wan J, Xu F, Lu J | title = Combining serum protein concentrations to diagnose schizophrenia: a preliminary exploration | journal = The Journal of Clinical Psychiatry | volume = 75 | issue = 8 | pages = e794–801 | date = August 2014 | pmid = 25191916 | doi = 10.4088/JCP.13m08772 }} It has been shown that BDNF mRNA levels are decreased in cortical layers IV and V of the dorsolateral prefrontal cortex of schizophrenic patients, an area associated with working memory.{{cite journal | vauthors = Ray MT, Shannon Weickert C, Webster MJ | title = Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders | journal = Translational Psychiatry | volume = 4 | issue = 5 | pages = e389 | date = May 2014 | pmid = 24802307 | pmc = 4035720 | doi = 10.1038/tp.2014.26 }}

{{See also|Epigenetics of depression#Brain-derived neurotrophic factor}}

The neurotrophic hypothesis of depression states that depression is associated with a decrease in the levels of BDNF.

Levels of both BDNF mRNA and BDNF protein are known to be up-regulated in epilepsy.{{cite journal | vauthors = Gall C, Lauterborn J, Bundman M, Murray K, Isackson P | title = Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain | journal = Epilepsy Research. Supplement | volume = 4 | pages = 225–45 | year = 1991 | pmid = 1815605 }}

• Epigenetics of depression § Brain-derived neurotrophic factor
• Epigenetics of schizophrenia § Methylation of BDNF
• Tropomyosin receptor kinase B § Agonists

{{Reflist|33em}}

• {{UCSC gene info|BDNF}}
• {{PDBe-KB2|P23560|Brain-derived neurotrophic factor}}

{{Hormones}}

{{Nerve growth factor family}}

{{Obsessive–compulsive disorder}}

{{Growth factor receptor modulators}}

{{DEFAULTSORT:Brain-Derived Neurotrophic Factor}}

Category:Neurotrophic factors

Category:Peptide hormones

Category:Growth factors

Category:Developmental neuroscience

Category:TrkB agonists