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Brain-derived neurotrophic factor
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor
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BDNF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBDNF, brain-derived neurotrophic factor, ANON2, BULN2, Brain-derived neurotrophic factor, brain derived neurotrophic factor
External IDsOMIM: 113505; MGI: 88145; HomoloGene: 7245; GeneCards: BDNF; OMA:BDNF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

627

12064

Ensembl

ENSG00000176697

ENSMUSG00000048482

UniProt

P23560

P21237

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 11: 27.65 – 27.72 MbChr 2: 109.51 – 109.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Brain-derived neurotrophic factor (BDNF), or abrineurin,[5] is a protein[6] that, in humans, is encoded by the BDNF gene.[7][8] BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.[9]

BDNF activates the TrkB tyrosine kinase receptor.[10][11]

Function

[edit]

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.[12][13] In the brain it is active in the hippocampus, cortex, and basal forebrain –areas vital to learning, memory, and higher thinking.[14] BDNF is also expressed in the retina, kidneys, prostate, motor neurons, and skeletal muscle, and is also found in saliva.[15][16]

BDNF itself is important for long-term memory.[17] 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.[18][19][20] 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.[21] 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.[22]

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.[16][23][24][25][26] Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well.[27]

Mechanism of action

[edit]

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).[28] It may also modulate the activity of various neurotransmitter receptors, including the Alpha-7 nicotinic receptor.[29] BDNF has also been shown to interact with the reelin signaling chain.[30] The expression of reelin by Cajal–Retzius cells goes down during development under the influence of BDNF.[31] The latter also decreases reelin expression in neuronal culture.

TrkB

[edit]

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,[10][11] 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]

LNGFR

[edit]

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.[32] When the p75 receptor is activated, it leads to activation of NFkB receptor.[32] 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.[33]

Expression

[edit]

The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11.[7][8] 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 .[34] There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression.[34] 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.[34][35] 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.[36] 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).[37] 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.[37] Activation of dopamine receptor D5 also promotes expression of BDNF in prefrontal cortex neurons.[38]

BDNF-AS

[edit]

The genomic locus encoding BDNF is structurally complex and also encodes BDNF-antisense (BDNF-AS; also known as BDNFOS or ANTI-BDNF).[39][40][41] BDNF-AS is a long non-coding RNA (lncRNA) transcribed from the opposite strand of the BDNF gene.[40] This lncRNA was identified in 2005 through searches in expressed sequence tag (EST) databases and subsequent RT-PCR experiments.[42][43] The gene encoding BDNF-AS is located on chromosome 11p14.1.[42] BDNF mRNA and BDNF-AS share a common overlapping region and form double-stranded RNA (dsRNA) duplexes.[40][41]

BDNF-AS regulates BDNF expression and can suppress BDNF mRNA.[40] In the human neocortex, regions with increased activity and BDNF expression exhibit reduced BDNF-AS expression.[39] Elevated BDNF-AS levels are associated with reduced BDNF expression and have been shown to promote neurotoxicity, increase apoptosis, and decrease cell viability.[40] 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.[40]

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.[41] 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.[41]

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.[40]

Common SNPs in BDNF gene

[edit]

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.[44][45]

Val66Met

[edit]

A common SNP in the BDNF gene is rs6265.[46] 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.[46][45] Val66Met is unique to humans.[46][45]

The mutation interferes with normal translation and intracellular trafficking of BDNF mRNA, as it destabilizes the mRNA and renders it prone to degradation.[46] 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.[46][45][47]

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,[45] anxiety disorders,[48] major depression,[49] and neurodegenerative diseases such as Alzheimer's and Parkinson's.[50]

A meta-analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.[51]

Role in synaptic transmission

[edit]

Glutamatergic signaling

[edit]

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 activity

[edit]

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.[52][53] 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.[52] 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.[52] 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.[54][55] Once activated, Fyn can bind to NR2B through its SH2 domain and mediate phosphorylation of its Tyr-1472 site.[56] Similar studies have suggested Fyn is also capable of activating NR2A although this was not found in the hippocampus.[57][58] 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.[57]

Synapse stability

[edit]

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.[59] 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.[60] It also appears that BDNF is able to influence Gl1 activity through its effects on NMDA receptor activity.[61] 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.[61] 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.[62] 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

[edit]

One mechanism through which BDNF appears to maintain elevated levels of neuronal excitation is through preventing GABAergic signaling activities.[63] 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 receptors tend to reduce their activity.[clarification needed] 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).[63] Similar effects could be obtained in BDNF knockout mice, but these effects were reversed by local application of BDNF.[63] This suggests BDNF increases excitatory synaptic signaling partly through the post-synaptic suppression of GABAergic signaling by activating PKC through its association with TrkB.[63] Once activated, PKC can reduce the amplitude of IPSCs through to GABAA receptor phosphorylation and inhibition.[63] 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.[64]

Synaptogenesis

[edit]

BDNF also enhances synaptogenesis. Synaptogenesis is dependent upon the assembly of new synapses and the disassembly of old synapses by β-adducin.[65] 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.[66] 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.[67] In post-synaptic neurons they can influence dendritic spine formation and retraction as well as AMPA receptor insertion and removal.[67] At their C-terminus, adducins possess a myristoylated alanine-rich C kinase substrate (MARCKS) domain which regulates their capping activity.[66] 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.[65][67]

Dendritogenesis

[edit]

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.[68] 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.[69] Thus, BDNF-induced trafficking of PSD-95 to dendrites stimulates actin remodeling and causes dendritic growth in response to BDNF.

Neurogenesis

[edit]

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.[32] 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.[32] BDNF can also promote NSC and NPC proliferation through Akt activation and PTEN inactivation.[70] Some studies suggest that BDNF may promote neuronal differentiation.[32][71]

Research

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Preliminary research has focused on the possible links between BDNF and clinical conditions, such as depression,[72] schizophrenia,[73] and Alzheimer's disease.[74]

Schizophrenia

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See also: Epigenetics of schizophrenia § Methylation of BDNF

Preliminary studies have assessed a possible relationship between schizophrenia and BDNF.[75] 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.[76]

Depression

[edit]
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.[72]

Epilepsy

[edit]

Levels of both BDNF mRNA and BDNF protein are known to be up-regulated in epilepsy.[77]

See also

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References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Brain-derived neurotrophic factor

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Brain-derived neurotrophic factor (BDNF) is a protein encoded by the located on , which provides instructions for producing a member of the family of structurally related polypeptide growth factors found primarily in the and . It is synthesized as a precursor protein (pro-BDNF) in the and cleaved into its mature form (approximately 13 kDa), which is secreted and acts as a key regulator of neuronal survival, growth, differentiation, and maintenance. BDNF exerts its effects mainly through binding to the high-affinity tyrosine kinase receptor TrkB and the low-affinity p75 receptor (p75NTR), triggering intracellular signaling pathways such as PLC, PI3K, and Ras-MAPK that promote synaptic plasticity, long-term potentiation (LTP), and neurogenesis. Discovered and purified in 1982 as a factor supporting neuronal survival and growth, BDNF is highly expressed in brain regions like the hippocampus, cortex, and , with expression levels increasing postnatally and stabilizing in adulthood. In the , it plays a pivotal role in guiding neuronal development, enhancing synaptic transmission, and modulating release, thereby contributing to processes like learning, formation, and adaptive responses to environmental stimuli. Beyond the brain, BDNF influences peripheral systems, including energy metabolism, appetite regulation, and body weight control, with circulating levels averaging around 92.5 pg/mL in human plasma and varying by factors such as age, gender, and —exercise, for instance, acutely elevates BDNF to support cognitive enhancement. Clinically, BDNF has significant implications across neurological, psychiatric, and metabolic disorders due to its involvement in and plasticity. Reduced BDNF levels are associated with neurodegenerative conditions like , , and , where it fails to mitigate neuronal loss and synaptic dysfunction. Genetic variations, such as the Val66Met polymorphism in the BDNF gene, impair protein and increase susceptibility to psychiatric disorders including , anxiety, , and eating disorders, as well as neurodevelopmental issues like autism spectrum disorder. Additionally, BDNF deletions contribute to severe and in syndromes like WAGR (often denoted as WAGRO), while its dysregulation links to opioid addiction, , and cardiovascular risks, positioning it as a potential therapeutic target for interventions like exercise regimens or pharmacological TrkB agonists.

Molecular Biology

Gene Structure and Discovery

Brain-derived neurotrophic factor (BDNF) was first identified in 1982 as a survival-promoting activity for sensory neurons from dorsal root ganglia in extracts of pig brain. This neurotrophic factor was purified from mammalian brain tissue by Yves-Alain Barde and colleagues, who isolated approximately 400 μg of the protein and demonstrated its distinct biological activity compared to (NGF). The discovery built on earlier work with NGF, highlighting BDNF's role in supporting neuronal survival . The BDNF gene in humans is located on the short arm of chromosome 11 at position 11p14.1 and spans approximately 70 kb of genomic DNA. It features a complex structure with nine 5' non-coding exons (I–IXa), each driven by individual promoters that enable tissue- and activity-specific transcription, spliced alternatively to a single 3' coding exon (IX) that encodes the prepro-BDNF polypeptide. This organization allows for multiple BDNF mRNA transcripts, contributing to regulated expression across different physiological contexts. The cDNA for BDNF was first cloned in 1989 from porcine , revealing its and confirming its expression as a 27 kDa precursor protein. Subsequent cloning efforts identified homologous genes in rat and human, establishing BDNF as the second member of the family, alongside NGF, (NT-3), and neurotrophin-4 (NT-4). BDNF exhibits high evolutionary conservation across vertebrates, with the mature protein showing over 90% identity between mammals and even greater similarity in functional domains compared to NGF, underscoring its preserved role in neural development.

Protein Structure and Processing

Brain-derived neurotrophic factor (BDNF) is initially synthesized as a precursor protein known as preproBDNF, consisting of 247 amino acids. This precursor undergoes cleavage of its N-terminal signal peptide (residues 1–18) in the endoplasmic reticulum to form proBDNF, a 229-amino-acid protein (residues 19–247) with an approximate molecular weight of 32 kDa. ProBDNF can then be further processed either intracellularly or extracellularly to yield the mature form of BDNF (mBDNF), a 119-amino-acid polypeptide (~14 kDa) that dimerizes to form a ~27-28 kDa homodimer. The of mBDNF, determined through of a BDNF/ heterodimer at 2.3 Å resolution, reveals a compact fold with a central core composed of antiparallel β-strands forming an extended β-sheet. This core is stabilized by three conserved bonds (Cys58–Cys108, Cys86–Cys107, and Cys90–Cys94), while variable loop regions extending from the β-sheet contribute to receptor specificity and ligand-receptor interactions. The dimeric interface involves hydrophobic contacts and hydrogen bonds, underscoring the structural homology among . Secretion of BDNF isoforms is differentially regulated in neurons. ProBDNF is primarily released via a constitutive secretory pathway from the trans-Golgi network, independent of neuronal activity. In contrast, mBDNF secretion occurs through activity-dependent from regulated dense-core vesicles, triggered by and calcium influx in hippocampal and cortical neurons. of proBDNF to mBDNF involves specific proteases acting at the dibasic cleavage site (Arg128–Ser129). Intracellularly, and proprotein convertases in the trans-Golgi network or secretory granules catalyze this cleavage to generate mBDNF prior to secretion. Extracellularly, and matrix metalloproteinases (such as MMP-3, MMP-7, and MMP-9) further cleave secreted proBDNF to mBDNF, with activity-dependent regulation of these enzymes modulating the proBDNF/mBDNF ratio in the synaptic cleft.

Expression Patterns

Central Nervous System Expression

Brain-derived neurotrophic factor (BDNF) exhibits prominent expression within specific regions of the central nervous system (CNS), particularly in areas associated with learning and memory. In both rodents and humans, high levels of BDNF mRNA and protein are observed in the hippocampus, including the CA1-CA3 pyramidal cell layers and dentate gyrus granule cells, as well as in the cerebral cortex across layers II-VI, the basal forebrain, and the amygdala. These patterns reflect BDNF's role in supporting neuronal populations critical for cognitive functions, with expression primarily localized to neurons such as pyramidal and granule cells. During development, BDNF expression in the CNS is low prenatally, with detectable mRNA emerging around embryonic day 15.5 in the hippocampus and later in the cortex. Postnatally, expression rises dramatically, peaking around postnatal days 7-14 in the hippocampus and cortex, a timeline that aligns with periods of intense and circuit maturation. This surge supports the establishment of synaptic connections during early brain development. BDNF expression in the CNS is highly regulated by neuronal activity. Neuronal , such as that induced by seizures or learning tasks, triggers calcium influx through L-type voltage-sensitive calcium channels, leading to activation of transcription factors like CREB and subsequent upregulation of BDNF transcription, particularly of activity-dependent exons such as exon IV. For instance, limbic seizures in adult rats rapidly increase BDNF mRNA in the and hippocampus within hours. External stimuli like exercise can further enhance this activity-dependent expression in hippocampal neurons. Regionally, BDNF shows specificity within the CNS, with lower expression in the and compared to the hippocampus and cortex. Under basal conditions, BDNF is largely absent from most glial cells, though it can be induced in under certain activity states.

Peripheral Expression and Regulation

Brain-derived neurotrophic factor (BDNF) is expressed in various components of nervous system, including sensory and motor neurons, where its mRNA has been detected in adult human tissues, supporting neuronal and regeneration. In the , BDNF is produced by retinal cells and other layers, promoting the and of these neurons during development and in response to . Beyond neuronal sites, BDNF expression occurs in non-neuronal peripheral tissues such as , where it is secreted in response to contractile activity, enhancing and fat oxidation; vascular , particularly in smooth muscle cells that express both BDNF and its receptors; and platelets, which store high concentrations of BDNF in α-granules and release it upon activation to modulate and . Peripheral BDNF expression is dynamically regulated by physiological and environmental factors. Physical exercise, particularly aerobic training, upregulates BDNF in peripheral tissues like skeletal muscle and elevates circulating levels, with acute high-intensity sessions increasing serum BDNF by approximately 25% in healthy adults. Hypoxia induces BDNF expression through activation of the hypoxia-inducible factor-1α (HIF-1α) pathway, which stabilizes BDNF mRNA and promotes adaptive responses in peripheral neurons and vascular cells. Similarly, inflammatory signals enhance BDNF via the nuclear factor-κB (NF-κB) pathway, as seen in endothelial and immune cells during acute stress, though chronic inflammation may suppress it. The majority of circulating BDNF in serum and plasma is derived from peripheral sources, particularly platelets, which store high concentrations in α-granules and release it upon activation. Although the produces BDNF, its contribution to circulating levels is small due to the blood-brain barrier, with potential modest increases during exercise. These peripheral contributions become more prominent post-exercise or in response to systemic stressors. status also influences circulating BDNF, as deficiency (serum 25(OH)D <30 ng/mL) correlates with lower levels, and high-dose supplementation (≥2000 IU/day for ≥12 weeks) raises serum BDNF by about 7% in deficient individuals, potentially via enhanced gene transcription in peripheral tissues. Recent reviews from 2024 highlight how exercise-induced peripheral BDNF elevations correlate with cognitive improvements in older adults, such as better executive function linked to higher plasma BDNF/irisin ratios following regular aerobic activity. In chronic conditions like , 12-week aerobic training programs increase serum BDNF and reduce fatigue severity, suggesting a role in alleviating systemic symptoms through peripheral mechanisms.

Receptors and Mechanisms of Action

TrkB Receptor Activation

TrkB, encoded by the NTRK2 gene, is a receptor tyrosine kinase that serves as the primary high-affinity receptor for brain-derived neurotrophic factor (BDNF). The receptor consists of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain essential for signal transduction. Upon binding of BDNF to the extracellular domain, TrkB undergoes dimerization, which is a critical step in its activation. The binding affinity of BDNF to TrkB is exceptionally high, with a dissociation constant (Kd) of approximately 10−11 M, enabling sensitive detection of the ligand even at low concentrations. This interaction induces conformational changes that activate the intracellular kinase domain, leading to autophosphorylation on specific residues, including Y490, Y785, and Y816. These phosphorylated tyrosines create docking sites for SH2-domain-containing adaptor proteins, such as Shc and phospholipase C-γ (PLC-γ), which initiate downstream signaling cascades. For instance, phosphorylation at Y490 recruits proteins involved in Ras-MAPK pathway , while Y785 and Y816 facilitate PLC-γ binding and subsequent . Mature BDNF (mBDNF), the processed form of BDNF, preferentially binds and activates TrkB to promote pro-survival and neurotrophic effects in neurons, distinguishing it from the precursor proBDNF, which has higher affinity for the p75NTR receptor and mediates opposing functions like . This specificity ensures that mBDNF-TrkB signaling supports neuronal maintenance and plasticity. Reduced BDNF protein production impairs TrkB receptor activation, leading to diminished neuronal survival, synaptic plasticity, dendritic growth, and cognitive support. For example, BDNF deficiency disrupts TrkB-mediated pathways essential for neuronal cell survival and synaptic maturation, as observed in models with reduced BDNF levels where neuronal survival is compromised and synaptic efficacy is reduced. Similarly, variants impairing BDNF-TrkB signaling result in decreased dendritic spine maintenance and impaired cognitive functions such as memory. TrkB is expressed in multiple isoforms due to of the NTRK2 transcript. The full-length isoform (TrkB.FL) contains the complete domain and is responsible for canonical signaling upon BDNF binding. In contrast, truncated isoforms such as TrkB.T1 and TrkB.T2 lack the kinase domain but retain the extracellular and transmembrane regions; these act as dominant negatives by heterodimerizing with TrkB.FL, thereby inhibiting its activation and BDNF-mediated responses. Truncated forms are particularly abundant in the adult brain and may modulate the intensity of trophic signaling.

p75NTR (LNGFR) Interactions

The p75 neurotrophin receptor (p75NTR), encoded by the NGFR , serves as a low-affinity receptor for all mammalian , including brain-derived neurotrophic factor (BDNF), with a dissociation constant (Kd) of approximately 1–10 nM. This binding occurs through the extracellular cysteine-rich domains of p75NTR, which recognize a conserved region in the . In contrast to the high-affinity binding of mature BDNF (mBDNF) to TrkB receptors, the precursor form proBDNF exhibits preferential affinity for p75NTR, often forming heterocomplexes with co-receptors such as sortilin to initiate signaling. These proBDNF-p75NTR-sortilin complexes promote pro-apoptotic pathways, particularly in contexts requiring neuronal refinement. In neuronal pruning during development, p75NTR activation by proBDNF triggers intracellular cascades involving c-Jun N-terminal kinase (JNK) and pathways, culminating in activation and of excess or inappropriate synapses and neurons. This mechanism helps sculpt neural circuits by eliminating competing projections, as evidenced in studies of hippocampal and cortical development where p75NTR-mediated balances neurotrophic support. The pro-apoptotic bias of p75NTR signaling contrasts with TrkB's pro-survival effects, ensuring precise wiring in the immature nervous system. As a co-receptor, p75NTR interacts directly with TrkB via both extracellular and intracellular domains, enhancing the specificity of TrkB activation for BDNF over other like NT-3 and NT-4/5, particularly at low ligand concentrations. This association also modulates the retrograde axonal transport of BDNF-TrkB complexes, facilitating their delivery from distal terminals to cell bodies for sustained signaling. Such cooperative functions refine responsiveness without altering overall binding affinity. p75NTR expression is prominent in the developing (CNS), including , hippocampus, , and spinal motoneurons, as well as in peripheral sensory and sympathetic neurons, where it supports circuit maturation. Levels are subsequently downregulated in the adult CNS and periphery, though re-expression occurs in response to or . This dynamic pattern aligns with p75NTR's role in developmental plasticity rather than baseline adult maintenance.

Intracellular Signaling Pathways

Upon ligand binding to the TrkB receptor, BDNF initiates three principal intracellular signaling cascades: the Ras-MAPK/ERK pathway, the PI3K-Akt pathway, and the PLCγ-IP3/Ca²⁺ pathway. These pathways mediate diverse neuronal responses, from survival to plasticity, through receptor autophosphorylation at specific tyrosine residues that recruit adaptor proteins and kinases. Reduced BDNF protein production diminishes the activation of these TrkB-mediated pathways, leading to impaired neuronal survival, synaptic plasticity, dendritic growth, and cognitive support. For instance, BDNF deficiency attenuates ERK and Akt signaling, resulting in reduced neuronal survival and dendritic arborization, while also impairing LTP and memory processes dependent on these cascades. The Ras-MAPK/ERK pathway drives gene transcription and neuronal differentiation by sequentially activating Ras, Raf, MEK, and ERK kinases, ultimately phosphorylating transcription factors such as CREB and c-Fos to induce expression of genes involved in growth and survival. This cascade is initiated via the adaptor proteins Shc and Grb2, which link TrkB to SOS and Ras, and features a positive feedback mechanism where activated ERK upregulates BDNF transcription, amplifying the signal. Temporal dynamics are notable: ERK phosphorylation occurs rapidly within minutes to support acute synaptic modulation, whereas sustained activation lasting hours facilitates long-term potentiation (LTP) and structural remodeling. With reduced BDNF, this pathway's diminished activity contributes to deficits in synaptic plasticity and cognitive functions, such as impaired learning and memory, as seen in models of BDNF reduction where LTP is attenuated. The PI3K-Akt pathway promotes anti-apoptotic neuronal survival and local protein synthesis by recruiting PI3K to phosphotyrosines on TrkB, generating PIP3 to activate Akt (also known as PKB), which in turn stimulates for translational control of dendritically localized mRNAs. A key aspect of cross-talk involves Akt-mediated phosphorylation and inhibition of FOXO transcription factors, suppressing pro-death genes and enhancing cell resilience. This pathway sustains signaling over extended periods, contributing to LTP and synaptic consolidation. Reduced BDNF impairs this pathway, leading to decreased neuronal survival and dendritic growth, with studies showing that BDNF-TrkB variants reduce Akt activation and associated survival under stress conditions. The PLCγ pathway supports by phosphorylating PLCγ at TrkB Tyr816, leading to of PIP2 into IP3 and diacylglycerol; IP3 triggers Ca²⁺ release from intracellular stores, activating Ca²⁺-dependent enzymes like CaMKII and promoting CREB for activity-dependent . This rapid Ca²⁺ influx, occurring within seconds to minutes of stimulation, coordinates with ERK and Akt for integrated effects on dynamics and transmitter release. Cross-talk among the pathways is evident, as ERK and Akt enhance PLCγ outputs while shared upstream adaptors like Shc ensure coordinated activation. Diminished BDNF levels reduce PLCγ activation, impairing synaptic plasticity and dendritic spine maturation, which in turn affects cognitive support mechanisms like memory consolidation.

Physiological Functions

Neurotrophic Effects

Brain-derived neurotrophic factor (BDNF) plays a crucial role in promoting the survival of various neuronal populations during development, particularly dopaminergic neurons in the mesencephalon, neurons in the , and sensory neurons in peripheral ganglia. In cultured mesencephalic neurons, BDNF increases survival rates by supporting differentiation and protecting against degeneration, with effects observed at concentrations as low as 10 ng/ml. Similarly, BDNF enhances survival and differentiation in embryonic cultures, stimulating activity and neurite outgrowth. For sensory neurons, BDNF acts as a target-derived trophic factor, rescuing nodose and neurons from during early postnatal stages. These survival-promoting effects are mediated primarily through activation of the TrkB receptor. Reduced BDNF protein production diminishes neuronal survival via impaired TrkB receptor signaling, leading to increased neuronal degeneration and reduced maintenance of neuronal populations, as observed in models of BDNF deficiency where cell death rates rise significantly. The necessity of BDNF for neuronal survival is underscored by phenotypes in BDNF mice, where homozygous mutants exhibit perinatal lethality, typically within 2-3 days after birth, due to severe respiratory and feeding difficulties. These mice display profound sensory deficits, including a drastic reduction (up to 60-70%) in the number of neurons in dorsal root ganglia, trigeminal ganglia, and nodose ganglia, leading to impaired coordination, balance, and . Heterozygous mutants survive to adulthood but show progressive sensorimotor impairments, highlighting BDNF's dose-dependent role in maintaining populations. BDNF also facilitates growth and branching, guiding target innervation through concentration gradients in both peripheral and targets. In Xenopus laevis models, BDNF gradients direct mandibular trigeminal axons toward peripheral targets like the cement gland, promoting arborization and precise innervation without affecting initial . In mammalian cortical cultures, BDNF acts as a chemoattractant, inducing turning and elongation in a cAMP-dependent manner, with effective gradients spanning 100-200 μm. These actions ensure appropriate topographic mapping, as seen in retinotectal projections where BDNF gradients refine axonal branching in the . Beyond structural support, BDNF provides metabolic sustenance to neurons by enhancing mitochondrial function and energy metabolism via upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In cortical neurons, BDNF treatment increases PGC-1α expression, leading to elevated , improved respiratory coupling, and higher ATP production, which buffers against . This pathway involves TrkB-mediated activation of downstream transcription factors, sustaining neuronal energy demands during growth and maintenance. In the adult nervous system, BDNF maintains neuronal integrity post-injury, particularly by preventing atrophy in facial motor neurons. Following facial nerve axotomy in neonatal rats, local BDNF infusion rescues motor neurons from soma shrinkage and degeneration, preserving cell size and cholinergic phenotype for up to two weeks post-injury. Retrograde transport of BDNF from target muscles further supports this maintenance, as demonstrated by its accumulation in axotomized facial nuclei.

Synaptic Plasticity and Transmission

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in modulating , the process underlying learning and , by influencing both pre- and postsynaptic mechanisms at synapses throughout the brain. BDNF enhances (LTP), a key form of synaptic strengthening, particularly in the hippocampus, where it promotes presynaptic neurotransmitter vesicle release and facilitates the trafficking of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid () receptors to the synaptic membrane. This dual action increases synaptic efficacy, as demonstrated in hippocampal slices where exogenous BDNF application potentiates LTP induction by strengthening excitatory transmission. Reduced BDNF protein production diminishes synaptic plasticity via disrupted TrkB receptor signaling, resulting in impaired LTP and reduced synaptic strengthening, which contributes to deficits in learning and memory processes. In synapses, BDNF signaling via its receptor TrkB elevates N-methyl-D-aspartate ( surface expression and increases density, thereby enhancing synaptic connectivity and responsiveness to stimuli. For synapses, BDNF shifts the balance between inhibition and excitation, refining activity by modulating inhibitory function and chloride homeostasis, which supports circuit maturation during development and activity-dependent plasticity. These effects collectively enable adaptive synaptic remodeling, with BDNF acting as a retrograde signal to coordinate presynaptic and postsynaptic changes. Long-term BDNF exposure stabilizes mature synapses by upregulating activity-regulated cytoskeleton-associated protein (Arc) and postsynaptic density protein 95 (PSD-95), proteins essential for maintaining synaptic structure and function over extended periods. Acutely, BDNF boosts the frequency of miniature excitatory postsynaptic currents (mEPSCs), reflecting rapid enhancement of spontaneous release without altering , thus fine-tuning synaptic transmission dynamics. These mechanisms distinguish BDNF's contributions to established synaptic function from broader neurotrophic support. BDNF-TrkB signaling contributes to homeostatic plasticity in cortical circuits, where it compensates for chronic changes in network activity by scaling synaptic strengths to preserve overall excitability. This homeostatic role ensures circuit stability amid fluctuating inputs, underscoring BDNF's integrative function in both Hebbian and non-Hebbian plasticity forms.

Neurogenesis and Neuronal Maturation

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in by enhancing the proliferation and survival of neural progenitor cells in the subgranular zone of the in the hippocampus. Infusion of BDNF directly into the adult rat hippocampus significantly increases the number of newly generated granule cells, demonstrating its capacity to promote in this neurogenic niche. This effect is mediated through activation of the TrkB receptor, which triggers downstream signaling via the PI3K/Akt pathway to support the differentiation and survival of these progenitors. Conditional of TrkB in the adult hippocampus markedly reduces , underscoring the essential nature of this BDNF-TrkB-Akt axis for maintaining neural progenitor dynamics in the . During neuronal development, BDNF drives dendritogenesis by promoting dendritic arborization and spine formation in cortical and hippocampal neurons. In layer 4 pyramidal neurons of the developing , endogenous BDNF stimulates dendritic growth, while opposing influences from NT-3 highlight its specific regulatory role in shaping dendritic architecture. In hippocampal neurons, BDNF application enhances proximal dendritic branching through CREB-dependent transcriptional mechanisms, leading to increased complexity and spine density that facilitate connectivity. These effects are activity-dependent, as BDNF's promotion of dendritic elaboration requires synaptic input to fully manifest during early postnatal stages. Reduced BDNF protein production diminishes dendritic growth via impaired TrkB receptor signaling, leading to reduced dendritic arborization, spine density, and overall neuronal connectivity, which can compromise cognitive functions dependent on mature neural circuits. BDNF also guides by facilitating the initial formation of synapses between axons and dendrites in embryonic neurons. In early developmental stages of the optic tectum, BDNF increases the density of synaptic sites on dendrites of tectal neurons, coordinating presynaptic and postsynaptic assembly. This involves BDNF's of spontaneous correlated network activity, which synchronizes and promotes in embryonic hippocampal cultures. Such mechanisms ensure proper wiring of nascent neural circuits during embryogenesis. In the context of neuronal maturation, BDNF accelerates the of new neurons into existing circuits, with effects peaking during when hippocampal is particularly robust. Local translation of BDNF from long 3' UTR mRNAs in dendrites of adult-born granule cells in the enhances their differentiation and maturation via signaling. This BDNF-mediated process supports the timely incorporation of these neurons into hippocampal networks, optimizing circuit function during the adolescent period of heightened plasticity.

Genetic Variations

Common SNPs and Their Effects

Single nucleotide polymorphisms (SNPs) in the BDNF gene are common genetic variations that can influence BDNF expression, protein function, and associated phenotypes. One of the most studied is rs6265, also known as Val66Met, which results in a valine-to-methionine substitution at codon 66 in the proBDNF protein; the Met allele frequency is approximately 20-30% in Caucasian populations and 40-50% in East Asian populations. While detailed effects of rs6265 are addressed elsewhere, it exemplifies how BDNF SNPs can broadly impact neurotrophic activity. Another frequent SNP, rs908867, located in the 5' regulatory region near the BDNF promoter, has been linked to variations in levels and response. Heterozygote carriers of rs908867 show improved response to compared to homozygotes, suggesting an influence on BDNF-mediated . This SNP also correlates with neurocognitive performance in , where certain alleles associate with deficits in executive function and . In individuals with mild , rs908867 variants are associated with reduced hippocampal volume on MRI imaging, indicating potential effects on brain structure. The intronic SNP rs2030324, situated in 4 of the , may affect splicing efficiency and mRNA processing, leading to altered BDNF transcript stability and expression. This polymorphism has been associated with increased risk of , with specific genotypes elevating susceptibility. In schizophrenia patients, rs2030324 influences cognitive domains such as performance, particularly in drug-naïve first-episode cases. Functional studies suggest that BDNF SNPs like rs2030324 contribute to inter-individual variability in plasma BDNF levels, potentially through changes in transcription or protein secretion. Overall, common BDNF SNPs such as rs908867 and rs2030324 modify BDNF function by altering transcription rates, mRNA splicing, protein secretion, or stability, resulting in heterogeneous BDNF signaling across populations. These variations are implicated in findings, including reduced hippocampal volumes in carriers of risk alleles, as observed in structural MRI studies of healthy and diseased cohorts.

Val66Met Polymorphism

The Val66Met polymorphism (rs6265) is a in the BDNF gene, characterized by a guanine-to-adenine (G>A) substitution in V. This change results in the replacement of (Val) with (Met) at amino acid position 66 within the prodomain of the proBDNF precursor protein. The polymorphism is common in populations of European descent, with the Met typically ranging from 20-30%. At the molecular level, the Val66Met substitution disrupts the intracellular trafficking and sorting of proBDNF into regulated secretory vesicles, thereby impairing activity-dependent BDNF release. This defect arises because the Met variant alters the conformation of the prodomain, preventing efficient packaging into dense-core vesicles and reducing depolarization-induced in neurons, particularly in the hippocampus, by approximately 18-30%. Consequently, mature BDNF levels available for synaptic function are diminished under activity-dependent conditions, while constitutive remains largely unaffected. Phenotypically, Met allele carriers exhibit structural and functional alterations in the brain. Meta-analyses have consistently shown that individuals with at least one Met have smaller hippocampal volumes compared to Val/Val homozygotes, with effect sizes indicating a modest but significant reduction of about 4-10% in total hippocampal gray matter. This polymorphism is also linked to impaired , as Met carriers demonstrate poorer performance on memory tasks involving hippocampal-dependent recall, accompanied by abnormal fMRI activation patterns in the hippocampus during encoding and retrieval. Additionally, the Met allele alters fear extinction processes; human and rodent studies reveal that Met carriers display slower extinction of conditioned fear responses, potentially due to reduced BDNF-mediated plasticity in the amygdala-hippocampal circuit. Recent analyses highlight the Met allele's complex role in stress-related traits. A 2023 meta-analysis on panic disorder cohorts found that the Met/Met genotype confers an increased risk for developing this anxiety disorder, with odds ratios indicating approximately 20-25% elevated susceptibility in Met/Met carriers compared to others. However, in specific high-stress environments, such as early-onset panic disorder, the Met allele may exert a protective effect by attenuating hyperreactive stress responses, as observed in genotype-stress interaction studies.

BDNF Antisense RNA (BDNF-AS)

BDNF antisense RNA (BDNF-AS), also known as BDNFOS, is a (lncRNA) that serves as a natural antisense transcript (NAT) to the BDNF , transcribed from the opposite strand and overlapping with BDNF IV. This genomic arrangement enables BDNF-AS to form double-stranded RNA duplexes with the complementary BDNF mRNA, which is a common mechanism for antisense-mediated regulation. The spans approximately 70 kb on 11p14.1 and produces multiple splice variants through alternative promoters and splicing, mirroring the complex structure of the BDNF locus itself. The primary function of BDNF-AS is to negatively regulate BDNF expression, primarily through epigenetic silencing rather than mRNA stabilization. It recruits the Polycomb Repressive Complex 2 (PRC2), including the subunit, to the BDNF promoter, increasing 27 trimethylation () marks and thereby repressing transcription. Experimental knockdown of BDNF-AS in neuronal models results in a 2- to 7-fold upregulation of BDNF mRNA and protein levels, confirming its suppressive role and highlighting potential for therapeutic intervention via antisense inhibition. Additionally, BDNF-AS can act as a competing endogenous (ceRNA), sponging microRNAs like miR-9-5p to indirectly modulate BDNF-related pathways. BDNF-AS is co-expressed with BDNF across various brain regions, exhibiting tissue- and region-specific patterns, with notable abundance in the and cortex. Its expression is dynamically upregulated in response to stress, as observed in early-onset alcohol use disorder models where BDNF-AS levels positively correlate with daily alcohol intake (r = 0.523) and contribute to reduced BDNF in the , impairing . In neurotoxicity contexts, such as hypoxia-ischemia or amyloid-beta exposure, BDNF-AS is elevated, promoting neuronal and while suppressing protective BDNF signaling. In , BDNF-AS has been implicated as a contributor to , with significantly higher plasma levels in late-stage patients compared to healthy controls, where it enhances BACE1 expression via miR-9-5p competition, exacerbating amyloid-beta accumulation and BDNF suppression. Silencing BDNF-AS in amyloid-beta-treated PC12 cells reduces , , and while restoring BDNF levels and cell viability, positioning it as a promising therapeutic target for derepressing BDNF to counteract neurodegeneration.

Clinical Relevance

Role in Neurodevelopmental and Neurodegenerative Disorders

Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopmental disorders, where its dysregulation contributes to impaired neuronal maturation. In , caused by in the MECP2 , BDNF transcripts are significantly reduced in affected brains, leading to compromised dendritic arborization and synaptic density. This reduction in BDNF protein production diminishes neuronal survival, synaptic plasticity, dendritic growth, and cognitive support via impaired TrkB receptor signaling, disrupting activity-dependent transcription of BDNF, which is essential for neurite growth and spine maturation, exacerbating the neurodevelopmental deficits characteristic of the disorder. Similarly, in autism spectrum disorders, altered BDNF signaling is associated with abnormal morphology and reduced dendritogenesis, contributing to connectivity issues in cortical and hippocampal regions through diminished neuronal survival and synaptic plasticity mediated by TrkB. Prenatal and early postnatal BDNF levels have predictive value for cognitive outcomes in neurodevelopment. In infants born to mothers with , lower serum BDNF levels at 12 months correlate with poorer language composite scores on developmental assessments, indicating that early BDNF deficits may forecast delays in cognitive and linguistic maturation via reduced TrkB signaling that impairs synaptic plasticity and dendritic growth. Higher BDNF concentrations in preterm infants, conversely, are linked to reduced odds of developmental domain failures, underscoring BDNF's protective role in early brain wiring and cognitive support. In neurodegenerative disorders, BDNF levels decline progressively, correlating with disease advancement and neuronal loss due to diminished neurotrophic effects on neuronal survival, synaptic plasticity, and dendritic growth via TrkB receptor signaling. In , oligomeric amyloid-beta peptides downregulate BDNF mRNA, particularly transcripts IV and V, impairing BDNF-TrkB signaling and promoting synaptic dysfunction, which exacerbates tau pathology by upregulating δ-secretase activity, which cleaves to form neurofibrillary tangles, and contributes to cognitive decline. In , BDNF mRNA expression is diminished by approximately 70% in the , largely due to the loss of BDNF-expressing neurons, with surviving neurons showing 20% lower levels and heightened vulnerability to degeneration through impaired TrkB-mediated survival and plasticity. aggregation further blocks BDNF-TrkB neurotrophic activities by binding to TrkB, inhibiting its trafficking and signaling, which accelerates . In , cortical BDNF levels decrease from the early symptomatic stage, correlating with motor dysfunction onset and enkephalinergic neuronal degeneration, thereby worsening disease progression and cognitive impairments via reduced TrkB signaling. Genetic variations in BDNF, such as the Val66Met polymorphism, modulate susceptibility to these disorders. These findings emphasize BDNF's mechanistic links to pathology across neurodevelopmental and neurodegenerative conditions.

Implications in Psychiatric Conditions

Brain-derived neurotrophic factor (BDNF) has been implicated in the of [major depressive disorder](/page/Major_depressive disorder) (MDD), with meta-analyses consistently showing that peripheral BDNF levels are significantly lower in individuals with MDD compared to healthy controls. This reduction is observed across serum and plasma measurements, reflecting potential deficits in neurotrophic support for mood-regulating circuits in the hippocampus and , where diminished BDNF protein production impairs neuronal survival, synaptic plasticity, dendritic growth, and cognitive support via TrkB receptor signaling. treatments, such as selective serotonin inhibitors (SSRIs), have been shown to elevate BDNF expression through of the extracellular signal-regulated (ERK) and cAMP response element-binding protein (CREB) signaling pathways, which may contribute to therapeutic . In , postmortem analyses of brain tissue reveal reduced BDNF expression in the hippocampus, suggesting impaired neurotrophic maintenance of neuronal integrity and synaptic function in regions critical for and , leading to diminished dendritic growth, synaptic plasticity, and cognitive support through impaired TrkB signaling. The Val66Met polymorphism in the BDNF gene (rs6265) is associated with this disorder, particularly influencing cognitive deficits such as and executive function impairments, as Met allele carriers exhibit altered BDNF secretion and hippocampal volume reductions. These genetic and molecular alterations underscore BDNF's role in the neurodevelopmental aspects of , linking reduced trophic support to symptom severity. A 2024 network of BDNF levels across psychiatric disorders identified disorder-specific patterns, with decreased peripheral BDNF in (BD), MDD, obsessive-compulsive disorder (OCD), (PD), and (SCZ) relative to controls, while levels were significantly elevated in (PTSD). In BD, lower BDNF correlates with mood episode severity during manic and depressive phases, potentially disrupting emotional regulation via impaired and cognitive support due to reduced TrkB signaling. Conversely, the increase in PTSD may reflect compensatory mechanisms in response to , though it contrasts with reductions seen in other anxiety-related conditions like OCD and PD. In , particularly (TLE), BDNF overexpression in the hippocampus promotes aberrant mossy fiber sprouting, a pathological reorganization of granule cell axons that contributes to hyperexcitability and propagation. This sprouting, observed in both human TLE tissue and animal models, is driven by seizure-induced BDNF upregulation, which enhances excitatory synaptic transmission and may perpetuate epileptogenic circuits.

BDNF as a Biomarker and Therapeutic Target

Serum levels of serve as a peripheral proxy for changes, reflecting alterations in brain BDNF expression and activity due to their correlation with levels. In and , serum BDNF concentrations are consistently decreased compared to healthy controls, with meta-analyses reporting significantly lower levels in AD patients (SMD = -0.282). Acute and chronic exercise interventions reliably elevate serum BDNF by 20-40%, with high-intensity protocols inducing immediate increases that support and cognitive benefits. Therapeutic strategies targeting BDNF focus on mimetics and delivery systems to overcome endogenous deficits. Small-molecule TrkB agonists, such as 7,8-dihydroxyflavone (7,8-DHF), mimic BDNF's neurotrophic effects by activating TrkB receptors, demonstrating preclinical in (ALS) models by preserving motor neurons and in AD models by reducing amyloid-beta pathology and synaptic loss. Derivatives like BrAD-R13, an optimized 7,8-DHF analog, have advanced to phase I/II clinical trials for mild-to-moderate AD as of 2024, showing improved cognitive outcomes without significant adverse effects. approaches, including (AAV)-mediated BDNF delivery, have restored dopamine neuron survival and function in animal models, such as MPTP-lesioned mice, by enhancing neurotransmission and mitigating mitochondrial dysfunction. These vectors target the , achieving sustained BDNF expression for up to 6 months post-administration. A primary challenge in BDNF-based therapies is the blood-brain barrier (BBB), which prevents significant delivery of BDNF across the BBB following . This necessitates alternative routes like intranasal or intracerebroventricular administration, though scalability remains limited. Non-pharmacological interventions, such as , boost endogenous BDNF by up to 30% through mechanisms involving increased hippocampal expression, while supplementation enhances BDNF levels by 15-25% in deficient individuals, with combined exercise-vitamin D protocols yielding synergistic in clinical trials. In precision medicine, BDNF , particularly for the Val66Met polymorphism, informs personalized selection, as 2025 meta-analyses indicate Met carriers exhibit faster response rates to selective serotonin inhibitors (SSRIs) in East Asian populations. This approach integrates BDNF levels with genetic data for optimized dosing and monitoring.

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