Category: signaling
Brain-derived neurotrophic factor (BDNF) is the principal neurotrophin of the adult mammalian brain — driver of activity-dependent synaptic plasticity (LTP), dendritic arborization, neurogenesis (hippocampal dentate gyrus), and neuronal survival. Synthesized as proBDNF (32 kDa), cleaved by furin/PC1 intracellularly or plasmin/MMP-9 extracellularly to mature BDNF (mBDNF, 14 kDa). mBDNF binds TrkB (high-affinity, Kd ~10 pM) → autophosphorylation → three parallel cascades: (1) Ras → Raf → MEK → ERK1/2 → CREB → gene transcription (positive feedback on BDNF + c-Fos + Arc); (2) PI3K → AKT → mTORC1 → S6K/4E-BP → cap-dependent protein synthesis (synaptic remodeling — the rapid-antidepressant axis hit by ketamine via NMDA-burst → mTOR); (3) PLCγ → IP3/DAG → CaMKII → presynaptic facilitation. ProBDNF preferentially binds p75NTR + sortilin → JNK → apoptosis (counter-regulatory; favored when proBDNF cleavage fails). Activity-dependent transcription: glutamate → NMDA → Ca²⁺ → CaMKIV → CREB; the BDNF promoter is also acetylation-sensitive — HDAC inhibitors (β-hydroxybutyrate, valproate) directly upregulate BDNF (Sleiman 2016). Antidepressant action of SSRIs is largely mediated by chronic BDNF/TrkB upregulation (weeks-scale — molecular basis of delayed onset); ketamine and 5-HT2A psychedelics bypass this delay via direct glutamate/mTOR engagement (Björkholm 2016). PGC-1α/FNDC5/irisin transduces exercise to hippocampal BDNF (Wrann 2013). Val66Met (rs6265) disrupts activity-dependent secretion — reduces LTP, increases anxiety/depression risk. Cross-links: mtor_signaling (PI3K-AKT-mTOR cascade), glutamate_receptor_pharmacology (NMDA-dependent transcription), serotonin_receptor_pharmacology (5-HT2A psychedelic transduction).