SORCS2 encodes a VPS10p-domain transmembrane receptor that serves as a critical coreceptor for neurotrophin signaling and synaptic plasticity regulation 1. The receptor functions as a homodimer that binds neurotrophins including NGF, proNGF, and proBDNF through its β-propeller domain 2. SORCS2 forms essential complexes with both p75NTR and TrkB receptors to mediate BDNF-dependent synaptic plasticity in hippocampal neurons 3. This dual interaction enables SORCS2 to facilitate both proBDNF-induced long-term depression via p75NTR and BDNF-induced long-term potentiation through activity-dependent TrkB binding and translocation to postsynaptic densities 3. Loss of SORCS2 eliminates hippocampal NMDA receptor-dependent plasticity and impairs BDNF-induced TrkB signaling cascades 3. The receptor also promotes Schwann cell apoptosis in response to proBDNF signaling [UniProt]. SORCS2 dysfunction is implicated in multiple neuropsychiatric disorders, with genetic variants associated with ADHD risk 45, bipolar disorder, and schizophrenia 3. Additionally, the proBDNF-SORCS2 axis suppresses osteogenesis and promotes inflammation in periodontal disease 6. Damaging SORCS2 variants compromise receptor stability and activity, potentially contributing to neurodevelopmental disorders through disrupted BDNF signaling 5.