Brain-derived neurotrophic factor signaling system (BDNF system) (BDNF system)

The Brain-derived neurotrophic factor (BDNF) signaling system is a fundamental neurotrophic pathway comprising the BDNF ligand and its primary receptors, Tropomyosin receptor kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR) (UniProt P23560, Q16620). This system is a master regulator of neuronal health, governing processes such as neuronal survival, differentiation, and synaptic plasticity, which underpins learning and memory (PubMed: 11487615). In the mature brain, BDNF-TrkB signaling is essential for maintaining synaptic strength and long-term potentiation. Dysregulation of the BDNF system is linked to the pathophysiology of numerous conditions, including major depressive disorder, where BDNF levels are often reduced, and neurodegenerative diseases like Alzheimer's and Huntington's (PubMed: 22252311). Therapeutic approaches target this system through TrkB agonists to provide neuroprotection, or via indirect modulators like ketamine that rapidly increase BDNF levels (PubMed: 21677754, 20118919). Additionally, the system is a target in oncology, where Trk inhibitors are used to treat rare but aggressive cancers driven by NTRK gene fusions (PubMed: 29466156).

Other names

BDNF-TrkB pathwayNeurotrophin signaling axisBDNF/NTRK2 systemBrain-derived neurotrophic factor receptor signaling

Pharmacological modulation of the BDNF system occurs through several distinct mechanisms: direct agonism of the TrkB receptor to mimic the neurotrophic effects of BDNF (e.g., 7,8-dihydroxyflavone) (PubMed: 20118919), indirect enhancement of BDNF expression and release through NMDA receptor antagonism (e.g., ketamine) or HDAC inhibition (e.g., valproic acid) (PubMed: 21677754, 19384925), and the use of small-molecule inhibitors to block Trk kinase activity in malignancies where NTRK gene fusions act as oncogenic drivers (e.g., larotrectinib) (PubMed: 29466156).