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Brain-derived neurotrophic factor
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<h2 id="function">Function</h2> <p>BDNF acts on certain <a href="/facts/Neuron/G7CyTVdH">neurons</a> of the <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a> and the <a href="/facts/Peripheral_nervous_system/KjVpVnHU">peripheral nervous system</a> expressing <a href="/facts/TrkB/rgnDhymj">TrkB</a>, helping to support survival of existing neurons, and encouraging growth and <a href="/facts/Cellular_differentiation/bCVqUG7w">differentiation</a> of new neurons and <a href="/facts/Synapse/vdMRJCUn">synapses</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> In the brain it is active in the <a href="/facts/Hippocampus/X7CqbP8X">hippocampus</a>, <a href="/facts/Cerebral_cortex/GpXosGHP">cortex</a>, and <a href="/facts/Basal_forebrain/eFB15xYw">basal forebrain</a> –areas vital to <a href="/facts/Learning/lehEKRjC">learning</a>, <a href="/facts/Memory/zucwQIEX">memory</a>, and higher thinking.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> BDNF is also expressed in the <a href="/facts/Retina/v0ISNX2S">retina</a>, <a href="/facts/Kidney/HBspPrv9">kidneys</a>, <a href="/facts/Prostate/mrBdSsf7">prostate</a>, <a href="/facts/Motor_neuron/LNqgmtYf">motor neurons</a>, and <a href="/facts/Skeletal_muscle/en1tVYFN">skeletal muscle</a>, and is also found in <a href="/facts/Saliva/gK4nvayc">saliva</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>BDNF itself is important for <a href="/facts/Long-term_memory/NvxgXP2y">long-term memory</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Although the vast majority of neurons in the <a href="/facts/Mammal/phSwTzBo">mammalian</a> brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural <a href="/facts/Stem_cell/qgB9dFrI">stem cells</a> in a process known as <a href="/facts/Neurogenesis/XSteTv8s">neurogenesis</a>. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Mice born without the ability to make BDNF have developmental defects in the brain and <a href="/facts/Sensory_nervous_system/05dM9sTQ">sensory nervous system</a>, and usually die soon after birth, suggesting that BDNF plays an important role in normal <a href="/facts/Neural_development/hSjrUxCn">neural development</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Other important neurotrophins structurally related to BDNF include <a href="/facts/NT-3/gED8r8C9">NT-3</a>, <a href="/facts/NT-4/jaYdw6Jx">NT-4</a>, and <a href="/facts/Nerve_growth_factor/lozj8usv">NGF</a>. </p><p>BDNF is made in the <a href="/facts/Endoplasmic_reticulum/DVbLA7GE">endoplasmic reticulum</a> and secreted from <a href="/facts/Dense-core_vesicle/YdycoGuR">dense-core vesicles</a>. It binds <a href="/facts/Carboxypeptidase_E/sXWr4azA">carboxypeptidase E</a> (CPE), and disruption of this binding has been proposed to cause the loss of sorting BDNF into dense-core vesicles. The <a href="/facts/Phenotype/vxWXKGLj">phenotype</a> for BDNF <a href="/facts/Knockout_mice/Aw50cobf">knockout mice</a> 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.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p><a href="/facts/Neurobiological_effects_of_physical_exercise/kVVntCLn">Certain types of physical exercise</a> 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.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> <a href="/facts/Niacin_(nutrient)/sgjmUWzx">Niacin</a> appears to upregulate BDNF and <a href="/facts/Tropomyosin_receptor_kinase_B/rgnDhymj">tropomyosin receptor kinase B</a> (TrkB) expression as well.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h2 id="mechanism-of-action">Mechanism of action</h2> <p>BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, <a href="/facts/TrkB/rgnDhymj">TrkB</a> (pronounced "Track B") and the <a href="/facts/LNGFR/Pm9SMrH3">LNGFR</a> (for <i>low-affinity nerve growth factor receptor</i>, also known as p75).<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> It may also modulate the activity of various neurotransmitter receptors, including the <a href="/facts/Alpha-7_nicotinic_receptor/Q4hcBmDE">Alpha-7 nicotinic receptor</a>.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> BDNF has also been shown to interact with the <a href="/facts/Reelin/PzkFDjn2">reelin</a> signaling chain.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> The expression of reelin by <a href="/facts/Cajal%25E2%2580%2593Retzius_cell/lfh2Tmzu">Cajal–Retzius cells</a> goes down during development under the influence of BDNF.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> The latter also decreases reelin expression in neuronal culture. </p> <h3>TrkB</h3> <p>The TrkB receptor is encoded by the <a href="/facts/NTRK2/rgnDhymj">NTRK2</a> gene and is member of a receptor family of tyrosine kinases that includes <a href="/facts/TrkA/N4hKvo9G">TrkA</a> and <a href="/facts/TrkC/C7QJ21ea">TrkC</a>. TrkB <a href="/facts/Autophosphorylation/2fxju7UD">autophosphorylation</a> is dependent upon its ligand-specific association with BDNF,<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> a widely expressed activity-dependent neurotrophic factor that regulates <a href="/facts/Synaptic_plasticity/rdVFxItN">plasticity</a> and is dysregulated following <a href="/facts/Hypoxia_(medical)/JWV04G89">hypoxic</a> injury. The activation of the BDNF-TrkB pathway is important in the development of short-term memory and the growth of neurons. </p> <h3>LNGFR</h3> <p>The role of the other BDNF receptor, <a href="/facts/Low-affinity_nerve_growth_factor_receptor/Pm9SMrH3">p75</a>, is less clear. While the TrkB receptor interacts with BDNF in a ligand-specific manner, all neurotrophins can interact with the p75 receptor.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> When the p75 receptor is activated, it leads to activation of <a href="/facts/NFkB/qcpt5vuQ">NFkB</a> receptor.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> Thus, neurotrophic signaling may trigger <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a> 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.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p> <h2 id="expression">Expression</h2> <p>The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> Structurally, BDNF transcription is controlled by eight different <a href="/facts/Promoter_(genetics)/YDYBzLfg">promoters</a>, each leading to different <a href="/facts/Transcription_(biology)/bDgp9HDN">transcripts</a> containing one of eight untranslated 5' <a href="/facts/Exons/8KWJtLuN">exons</a> (I to VIII) <a href="/facts/RNA_splicing/a2QEvCRI">spliced</a> 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 <a href="/facts/CAMP_response_element/ug1kE9j0">Cre</a> regulatory component, suggesting a putative role for the transcription factor <a href="/facts/CREB/ug1kE9j0">CREB</a> and the source of BDNF's activity-dependent effects .<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> Stimulus-mediated neuronal excitation can lead to <a href="/facts/NMDA_receptor/BqMhXEbU">NMDA receptor</a> activation, triggering a calcium influx. Through a protein signaling cascade requiring <a href="/facts/Extracellular_signal-regulated_kinases/NRmUI80z">Erk</a>, <a href="/facts/Ca2%252B%2fcalmodulin-dependent_protein_kinase_II/hklT8LuH">CaM KII/IV</a>, <a href="/facts/PI3K/e5rtq0VG">PI3K</a>, and <a href="/facts/Phospholipase_C/Cuo6V7gU">PLC</a>, 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.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a><a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> 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.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> 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 <a href="/facts/Basic_helix%25E2%2580%2593loop%25E2%2580%2593helix/yqfuWejn">basic helix–loop–helix</a> transcription factor protein 2 (<a href="/facts/BHLHB2/ThvSo14C">BHLHB2</a>).<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> 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.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> Activation of <a href="/facts/Dopamine_receptor_D5/VAAvdkLS">dopamine receptor D5</a> also promotes expression of BDNF in <a href="/facts/Prefrontal_cortex/dypYIrwx">prefrontal cortex</a> neurons.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> </p> <h2 id="bdnf-as">BDNF-AS</h2> <p>The genomic locus encoding BDNF is structurally complex and also encodes BDNF-antisense (BDNF-AS; also known as BDNFOS or ANTI-BDNF).<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a><a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> BDNF-AS is a long non-coding RNA (lncRNA) transcribed from the opposite strand of the BDNF gene.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> This lncRNA was identified in 2005 through searches in expressed sequence tag (EST) databases and subsequent RT-PCR experiments.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a><a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> The gene encoding BDNF-AS is located on chromosome 11p14.1.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> BDNF mRNA and BDNF-AS share a common overlapping region and form double-stranded RNA (dsRNA) duplexes.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a><a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> </p><p>BDNF-AS regulates BDNF expression and can suppress BDNF mRNA.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> In the human neocortex, regions with increased activity and BDNF expression exhibit reduced BDNF-AS expression.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> Elevated BDNF-AS levels are associated with reduced BDNF expression and have been shown to promote neurotoxicity, increase apoptosis, and decrease cell viability.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> 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.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> 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.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> </p> <h2 id="common-snps-in-bdnf-gene">Common SNPs in BDNF gene</h2> <p>BDNF has several known <a href="/facts/Single_nucleotide_polymorphism/Qy5Y2wom">single nucleotide polymorphisms</a> (SNP), including, but not limited to, rs6265, C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442. <a href="/facts/Rs6265/IGXbd7P9">rs6265</a> is the most studied <a href="/facts/Single-nucleotide_polymorphism/Qy5Y2wom">SNP</a> in the <i>BDNF</i> gene.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a><a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> </p> <h3>Val66Met</h3> <p>A common <a href="/facts/Single-nucleotide_polymorphism/Qy5Y2wom">SNP</a> in the BDNF gene is rs6265.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> 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.<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a><a class="footnote-ref" id="fnref:64" href="#fn:64"><sup>64</sup></a> Val66Met is unique to humans.<a class="footnote-ref" id="fnref:65" href="#fn:65"><sup>65</sup></a><a class="footnote-ref" id="fnref:66" href="#fn:66"><sup>66</sup></a> </p><p>The mutation interferes with normal translation and intracellular trafficking of BDNF mRNA, as it destabilizes the mRNA and renders it prone to degradation.<a class="footnote-ref" id="fnref:67" href="#fn:67"><sup>67</sup></a> 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 <a href="/facts/Sortilin_1/tLXb7gTe">sortilin</a> binds; and sortilin is essential for normal trafficking.<a class="footnote-ref" id="fnref:68" href="#fn:68"><sup>68</sup></a><a class="footnote-ref" id="fnref:69" href="#fn:69"><sup>69</sup></a><a class="footnote-ref" id="fnref:70" href="#fn:70"><sup>70</sup></a> </p><p>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,<a class="footnote-ref" id="fnref:71" href="#fn:71"><sup>71</sup></a> <a href="/facts/Anxiety_disorder/wh9zFH1V">anxiety disorders</a>,<a class="footnote-ref" id="fnref:72" href="#fn:72"><sup>72</sup></a> <a href="/facts/Major_depressive_disorder/l2lQeWqr">major depression</a>,<a class="footnote-ref" id="fnref:73" href="#fn:73"><sup>73</sup></a> and neurodegenerative diseases such as Alzheimer's and <a href="/facts/Parkinson%2527s_disease/xpekKj6x">Parkinson's</a>.<a class="footnote-ref" id="fnref:74" href="#fn:74"><sup>74</sup></a> </p><p>A meta-analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.<a class="footnote-ref" id="fnref:75" href="#fn:75"><sup>75</sup></a> </p> <h2 id="role-in-synaptic-transmission">Role in synaptic transmission</h2> <h3>Glutamatergic signaling</h3> <p><a href="/facts/Glutamate_(neurotransmitter)/GRqBSJ1P">Glutamate</a> is the brain's major excitatory <a href="/facts/Neurotransmitter/LlpYFSU3">neurotransmitter</a> and its release can trigger the <a href="/facts/Depolarization/qGX8lFXE">depolarization</a> of <a href="/facts/Postsynaptic/M1x5rhz7">postsynaptic</a> neurons. <a href="/facts/AMPA/jeQWeMVw">AMPA</a> and <a href="/facts/NMDA/7jnfxMBU">NMDA</a> receptors are two <a href="/facts/Ionotropic_receptor/gN9RkNC2">ionotropic</a> glutamate receptors involved in <a href="/facts/Glutamic_acid/7oXbNcvu">glutamatergic neurotransmission</a> and essential to learning and memory via <a href="/facts/Long-term_potentiation/AbuJmBeo">long-term potentiation</a>. While <a href="/facts/AMPA_receptor/FJHDlvkg">AMPA receptor</a> activation leads to depolarization via sodium influx, <a href="/facts/NMDA_receptor/BqMhXEbU">NMDA receptor</a> 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, <a href="/facts/Dendrite/bwv8MABY">dendritogenesis</a>, and synaptic stabilization. </p> <h4>NMDA receptor activity</h4> <p>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.<a class="footnote-ref" id="fnref:76" href="#fn:76"><sup>76</sup></a><a class="footnote-ref" id="fnref:77" href="#fn:77"><sup>77</sup></a> 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.<a class="footnote-ref" id="fnref:78" href="#fn:78"><sup>78</sup></a> The mechanism underlying this activity is dependent upon both <a href="/facts/Extracellular_signal-regulated_kinases/NRmUI80z">ERK</a> and <a href="/facts/Protein_kinase_C/6WSQgAWv">PKC</a> signaling pathways, each acting individually, and all NR1 phosphorylation activity is lost if the TrKB receptor is blocked.<a class="footnote-ref" id="fnref:79" href="#fn:79"><sup>79</sup></a> 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 <a href="/facts/NR2B/GllS9Fpu">NR2B</a> subunit. BDNF signaling leads to the autophosphorylation of the intracellular domain of the TrkB receptor (ICD-TrkB). Upon autophosphorylation, <a href="/facts/FYN/qCAEbIAb">Fyn</a> associates with the pICD-TrkB through its <a href="/facts/SH2_domain/1kEmHvzY">Src homology domain 2</a> (SH2) and is phosphorylated at its Y416 site.<a class="footnote-ref" id="fnref:80" href="#fn:80"><sup>80</sup></a><a class="footnote-ref" id="fnref:81" href="#fn:81"><sup>81</sup></a> Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr-1472 site.<a class="footnote-ref" id="fnref:82" href="#fn:82"><sup>82</sup></a> Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus.<a class="footnote-ref" id="fnref:83" href="#fn:83"><sup>83</sup></a><a class="footnote-ref" id="fnref:84" href="#fn:84"><sup>84</sup></a> 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.<a class="footnote-ref" id="fnref:85" href="#fn:85"><sup>85</sup></a> </p> <h4>Synapse stability</h4> <p>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.<a class="footnote-ref" id="fnref:86" href="#fn:86"><sup>86</sup></a> It was previously mentioned that <a href="/facts/AMPA/jeQWeMVw">AMPA</a> 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 <a href="/facts/GluR1/dhRPruvI">GluR1</a> via PKC- and CaMKII-mediated Ser-831 phosphorylation.<a class="footnote-ref" id="fnref:87" href="#fn:87"><sup>87</sup></a> It also appears that BDNF is able to influence Gl1 activity through its effects on NMDA receptor activity.<a class="footnote-ref" id="fnref:88" href="#fn:88"><sup>88</sup></a> BDNF significantly enhanced the activation of GluR1 through phosphorylation of tyrosine830, an effect that was abolished in either the presence of a specific <a href="/facts/NR2B/GllS9Fpu">NR2B</a> antagonist or a trk receptor tyrosine kinase inhibitor.<a class="footnote-ref" id="fnref:89" href="#fn:89"><sup>89</sup></a> 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 <a href="/facts/Neogenin/gwaIH1Y6">Neogenin</a> which are essential for spine enlargement and activity.<a class="footnote-ref" id="fnref:90" href="#fn:90"><sup>90</sup></a> 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. </p> <h3>GABAergic signaling</h3> <p>One mechanism through which BDNF appears to maintain elevated levels of neuronal excitation is through preventing <a href="/facts/GABA/vRTeQQUG">GABAergic</a> signaling activities.<a class="footnote-ref" id="fnref:91" href="#fn:91"><sup>91</sup></a> While glutamate is the brain's major excitatory neurotransmitter and phosphorylation normally activates receptors, <a href="/facts/GABA/vRTeQQUG">GABA</a> is the brain's primary inhibitory neurotransmitter and phosphorylation of <a href="/facts/GABAA_receptor/6G4rAGb3">GABAA receptors</a> tend to reduce their activity. Blockading BDNF signaling with a tyrosine kinase inhibitor or a PKC inhibitor in wild type mice produced significant reductions in spontaneous <a href="/facts/Action_potential/Sz8yCRqx">action potential</a> frequencies that were mediated by an increase in the amplitude of GABAergic <a href="/facts/Inhibitory_postsynaptic_potential/Jfm13Wkn">inhibitory postsynaptic currents</a> (IPSC).<a class="footnote-ref" id="fnref:92" href="#fn:92"><sup>92</sup></a> Similar effects could be obtained in BDNF knockout mice, but these effects were reversed by local application of BDNF.<a class="footnote-ref" id="fnref:93" href="#fn:93"><sup>93</sup></a> This suggests BDNF increases excitatory synaptic signaling partly through the post-synaptic suppression of GABAergic signaling by activating PKC through its association with TrkB.<a class="footnote-ref" id="fnref:94" href="#fn:94"><sup>94</sup></a> Once activated, PKC can reduce the amplitude of IPSCs through to GABAA receptor phosphorylation and inhibition.<a class="footnote-ref" id="fnref:95" href="#fn:95"><sup>95</sup></a> 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.<a class="footnote-ref" id="fnref:96" href="#fn:96"><sup>96</sup></a> </p> <h3>Synaptogenesis</h3> <p>BDNF also enhances synaptogenesis. <a href="/facts/Synaptogenesis/1fVRWK6e">Synaptogenesis</a> is dependent upon the assembly of new synapses and the disassembly of old synapses by <a href="/facts/ADD2/cV2I3rfg">β-adducin</a>.<a class="footnote-ref" id="fnref:97" href="#fn:97"><sup>97</sup></a> Adducins are membrane-skeletal proteins that cap the growing ends of <a href="/facts/Actin/Hu3qIUL9">actin</a> filaments and promote their association with spectrin, another cytoskeletal protein, to create stable and integrated cytoskeletal networks.<a class="footnote-ref" id="fnref:98" href="#fn:98"><sup>98</sup></a> 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.<a class="footnote-ref" id="fnref:99" href="#fn:99"><sup>99</sup></a> In post-synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal.<a class="footnote-ref" id="fnref:100" href="#fn:100"><sup>100</sup></a> At their C-terminus, adducins possess a myristoylated alanine-rich C kinase substrate (MARCKS) domain which regulates their capping activity.<a class="footnote-ref" id="fnref:101" href="#fn:101"><sup>101</sup></a> 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.<a class="footnote-ref" id="fnref:102" href="#fn:102"><sup>102</sup></a><a class="footnote-ref" id="fnref:103" href="#fn:103"><sup>103</sup></a> </p> <h3>Dendritogenesis</h3> <p>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.<a class="footnote-ref" id="fnref:104" href="#fn:104"><sup>104</sup></a> <a href="/facts/PSD-95/d23IStkv">PSD-95</a> localizes the actin-remodeling GTPases, <a href="/facts/Rac_(GTPase)/JPR3AF2V">Rac</a> and <a href="/facts/Rho_family_of_GTPases/RvAaNbp3">Rho</a>, to synapses through the binding of its PDZ domain to <a href="/facts/Kalirin/0MgP6oer">kalirin</a>, increasing the number and size of spines.<a class="footnote-ref" id="fnref:105" href="#fn:105"><sup>105</sup></a> Thus, BDNF-induced trafficking of <a href="/facts/PSD-95/d23IStkv">PSD-95</a> to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF. </p> <h2 id="neurogenesis">Neurogenesis</h2> <p>Laboratory studies indicate that BDNF may play a role in <a href="/facts/Neurogenesis/XSteTv8s">neurogenesis</a>. 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.<a class="footnote-ref" id="fnref:106" href="#fn:106"><sup>106</sup></a> 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 <a href="/facts/Caspase-3/FpjEwtwR">caspase-3</a>.<a class="footnote-ref" id="fnref:107" href="#fn:107"><sup>107</sup></a> BDNF can also promote NSC and NPC proliferation through <a href="/facts/Akt/odL6duk1">Akt</a> activation and <a href="/facts/Phosphatidylinositol-3%2c4%2c5-trisphosphate_3-phosphatase/9bkmxe6d">PTEN</a> inactivation.<a class="footnote-ref" id="fnref:108" href="#fn:108"><sup>108</sup></a> Some studies suggest that BDNF may promote neuronal differentiation.<a class="footnote-ref" id="fnref:109" href="#fn:109"><sup>109</sup></a><a class="footnote-ref" id="fnref:110" href="#fn:110"><sup>110</sup></a> </p> <h2 id="research">Research</h2> <p>Preliminary research has focused on the possible links between BDNF and clinical conditions, such as <a href="/facts/Clinical_depression/l2lQeWqr">depression</a>,<a class="footnote-ref" id="fnref:111" href="#fn:111"><sup>111</sup></a> <a href="/facts/Schizophrenia/FMP4lQ57">schizophrenia</a>,<a class="footnote-ref" id="fnref:112" href="#fn:112"><sup>112</sup></a> and <a href="/facts/Alzheimer%2527s_disease/w7Ad6tdg">Alzheimer's disease</a>.<a class="footnote-ref" id="fnref:113" href="#fn:113"><sup>113</sup></a> </p> <h3>Schizophrenia</h3> <p class="note">See also: <a href="/facts/Epigenetics_of_schizophrenia/MDaRpHzI">Epigenetics of schizophrenia § Methylation of BDNF</a></p> <p>Preliminary studies have assessed a possible relationship between <a href="/facts/Schizophrenia/FMP4lQ57">schizophrenia</a> and BDNF.<a class="footnote-ref" id="fnref:114" href="#fn:114"><sup>114</sup></a> 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.<a class="footnote-ref" id="fnref:115" href="#fn:115"><sup>115</sup></a> </p> <h3>Depression</h3> <p class="note">See also: <a href="/facts/Epigenetics_of_depression/3BYSR6RT">Epigenetics of depression § Brain-derived neurotrophic factor</a></p> <p>The neurotrophic hypothesis of depression states that depression is associated with a decrease in the levels of BDNF.<a class="footnote-ref" id="fnref:116" href="#fn:116"><sup>116</sup></a> </p> <h3>Epilepsy</h3> <p>Levels of both BDNF mRNA and BDNF protein are known to be up-regulated in <a href="/facts/Epilepsy/wawyp56a">epilepsy</a>.<a class="footnote-ref" id="fnref:117" href="#fn:117"><sup>117</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Epigenetics_of_depression/3BYSR6RT">Epigenetics of depression § Brain-derived neurotrophic factor</a></li> <li><a href="/facts/Epigenetics_of_schizophrenia/MDaRpHzI">Epigenetics of schizophrenia § Methylation of BDNF</a></li> <li><a href="/facts/Tropomyosin_receptor_kinase_B/rgnDhymj">Tropomyosin receptor kinase B § Agonists</a></li></ul> <h2 id="external-links">External links</h2> <ul><li>Human <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=BDNF"><i>BDNF</i></a> genome location and <a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=BDNF"><i>BDNF</i></a> gene details page in the <a href="/facts/UCSC_Genome_Browser/kwumPyLb">UCSC Genome Browser</a>.</li> <li>Overview of all the structural information available in the <a href="/facts/Protein_Data_Bank/oUhq4ABD">PDB</a> for <a href="/facts/UniProt/lfDDHjAl">UniProt</a>: <i><a href="https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P23560">P23560</a></i> (Brain-derived neurotrophic factor) at the <a href="/facts/PDBe-KB/p1WX7lPH">PDBe-KB</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Anti-Brain Derived Neurotrophic Factor Antibody, pro". sigmaaldrich.com. 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