BDNF / TrkB neurotrophic signaling

Category: signaling

Overview

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).

Organ Systems

Pathway Steps

  1. BDNF gene (chr 11p14.1) → proBDNF (32 kDa) — via CREB-driven transcription (activity-dependent) → ER translation; promoter IV is the activity-responsive exon. The BDNF gene (11p14.1) has multiple promoters and 5′ exons spliced to a common coding exon, allowing tissue- and activity-specific expression. The common Val66Met prodomain polymorphism impairs activity-dependent BDNF secretion and is linked to memory and mood phenotypes. Translation yields the 32-kDa precursor proBDNF.
  2. proBDNF (32 kDa) → mBDNF (14 kDa) — via furin / PC1 intracellularly OR plasmin / MMP-9 extracellularly; balance determines TrkB vs p75NTR signaling. proBDNF is cleaved (by furin/proconvertases intracellularly or plasmin/MMPs extracellularly) to the 14-kDa mature BDNF. This is a regulatory switch, not mere processing: proBDNF and mBDNF have opposing actions, so the balance of cleavage decides whether the signal promotes survival or synaptic pruning.
  3. mBDNF (14 kDa) → TrkB-P (autophosphorylated) — via TrkB high-affinity binding (Kd ~10 pM); receptor dimerization → trans-autophosphorylation Y515/Y816. Mature BDNF binds its high-affinity receptor TrkB, driving dimerization and trans-autophosphorylation of cytoplasmic tyrosines. These phosphotyrosines are docking sites that launch three downstream cascades — the basis for BDNF’s roles in neuronal survival, synaptic plasticity, and the structural changes underlying learning.
  4. TrkB-P (autophosphorylated) → ERK1/2 → CREB → gene transcription — via Ras → Raf → MEK → ERK; positive feedback on BDNF; LTP-associated plasticity genes. Phospho-TrkB recruits Shc/Grb2/SOS to activate Ras-ERK1/2, which phosphorylates CREB to transcribe plasticity/survival genes (including BDNF itself — a positive-feedback loop). This ERK-CREB arm is central to long-term potentiation and to the delayed gene-expression program of antidepressant action.
  5. TrkB-P (autophosphorylated) → AKT → mTORC1 → cap-dependent translation — via PI3K → PDK1/AKT → mTORC1 → S6K + 4E-BP1 phosphorylation; ketamine rapid-antidepressant pathway. A second arm activates PI3K-AKT, which relieves mTORC1 inhibition to drive cap-dependent local protein synthesis at synapses. This rapid, transcription-independent translation supplies proteins for dendritic-spine remodeling — the arm implicated in the fast antidepressant effect of ketamine via BDNF-TrkB-mTOR.
  6. TrkB-P (autophosphorylated) → IP3 / DAG → CaMKII — via PLCγ activation; presynaptic vesicle release facilitation. The third arm runs through PLCγ to IP3/DAG, raising intracellular Ca²⁺ and activating CaMKII (and PKC). This calcium arm couples BDNF to the same kinases that read synaptic activity, directly modulating LTP and glutamatergic transmission — tying neurotrophic signaling to moment-to-moment plasticity.
  7. proBDNF (32 kDa) → JNK → apoptosis — via p75NTR + sortilin co-receptor; counter-regulatory branch favored if cleavage fails. Opposing the survival signals, uncleaved proBDNF binds the p75NTR/sortilin complex to activate JNK and pro-apoptotic signaling. So one gene yields antagonistic ligands — mBDNF/TrkB for survival and plasticity, proBDNF/p75 for apoptosis and LTD — a yin-yang that sculpts neural circuits.

Known Modulators

References