SCN2B Drives Depression-like Phenotypes in Mice by Suppressing BDNF Signaling via Its Intracellular Domain NICD

The rising global burden of depression necessitates novel mechanistic insights and therapeutic targets. Voltage-gated sodium channel β2-subunit (Navβ2, coded by SCN2B) has been implicated in neuropsychiatric disorders, yet its role in depression remains unexplored. Here, we identify SCN2B as a previously unrecognized driver of depression-like pathophysiology. Using SCN2B-overexpressing (SCN2B-OV) mice across different ages (1, 12, and 20 months) and CRISPR- engineered Navβ2^V173A,V175K mice with selective reduction of the Navβ2 intracellular domain (NICD), we combined behavioral phenotyping, electrophysiology, neurotransmitter profiling, and molecular analyses, with chronic unpredictable mild stress (CUMS) as an environmental challenge. SCN2B-OV mice exhibited accelerated depression-like phenotypes, including anhedonia (sucrose preference 52.42% reduction, P<0.05), behavioral despair (forced swim test immobility 67.42% increase, P<0.05), and cognitive deficits (Y-maze alternation 50.90% reduction, P<0.05), independent of natural aging. Electrophysiologically, SCN2B overexpression induced a striking prefrontal-hippocampal imbalance: prefrontal cortex (PFC) became hyperexcitable (glutamate release increased by 64.7%; sEPSC amplitude increased 2.05-fold, P<0.05), whereas the hippocampus showed synaptic suppression (GABA release reduced by 32.65%; sIPSC frequency reduced by 66.67%, P<0.05). Mechanistically, SCN2B overexpression suppressed BDNF/TrkB/PI3K/AKT signaling axis (BDNF reduced by 53.17%; p-TrkB reduced by 63.62%, P<0.05), accompanied by decreased synaptic proteins (PSD95 43.45%, synapsin I 40.31%, P<0.05). Remarkably, NICD-reduced Navβ2^V173A,V175K mice were fully resistant to CUMS-induced behavioral and neurotransmitter deficits, establishing NICD as a critical mediator of stress vulnerability. Collectively, these findings unravel a causal pathway in which SCN2B overexpression drives NICD-dependent suppression of BDNF signaling, leading to region-specific excitatory/inhibitory imbalance, synaptic disintegration, and depression-like phenotypes. Targeting Navβ2 proteolysis to block NICD generation may thus represent a novel therapeutic strategy for mood disorders.