Tetrodotoxin-resistant NaV1.5 channels regulate excitability of lateral septum neurons and emotion behaviors of chronically stressed mice

Lateral septum (LS) plays crucial roles in regulating various emotional behaviors. The molecular mechanism governing the excitability of LS neuron (LSN) remains unclear. Using single-nucleus RNA sequencing (snRNA-seq) and immunostaining, we detected high expression levels of Scn5a , the cardiac TTX-resistant voltage-gated Na + channel (Na V ) subtype across many transcriptomic LSN types, and accumulation of its channel protein Na V 1.5 at the axon initial segment. Activation of Na V 1.5 alone is sufficient to generate action potentials, particularly from a hyperpolarized membrane potential. Knocking out Na V 1.5 from LSNs reduces spiking activity and decreases anxiety and depression levels in chronically stressed mice, but not in unstressed ones. Importantly, acute treatment with the antiarrhythmic agent flecainide can diminish the TTX-resistant currents and alleviate the anxiety- and depression-like behaviors of stressed mice. Together, our results reveal a critical role of Na V 1.5 channels in governing LSN excitability and identify a potential drug target for a rapid control of emotional disorders.