Sodium channel β1 subunit localizes to axon initial segments of excitatory and inhibitory neurons and shows regional heterogeneity in mouse brain

The β1 subunit of voltage-gated sodium channels, Na_vβ1, plays multiple roles in neurons spanning electrophysiological modulation of sodium channel α subunits to cell adhesion and neurite outgrowth. This study used immunohistochemistry to investigate Na_vβ1 subneuronal and regional expression. Na_vβ1 was enriched at axon initial segments (AIS) and nodes of Ranvier. Na_vβ1 expression at the AIS was detected throughout the brain, predominantly in the hippocampus, cortex, and cerebellum. Despite expression of Na_vβ1 in both excitatory and inhibitory AIS, it displayed a marked and fine-grained heterogeneity of expression. Such heterogeneity could have important implications for the tuning of single neuronal and regional excitability, especially in view of the fact that Na_vβ1 coexpressed with Na_v1.1, Na_v1.2, and Na_v1.6 subunits. The disruption of Na_vβ1 AIS expression by a human epilepsy-causing C121W genetic mutation in Na_vβ1 was also investigated using a mouse model. AIS expression of Na_vβ1 was reduced by approximately 50% in mice heterozygous for the C121W mutation and was abolished in homozygotes, suggesting that loss of Na_vα subunit modulation by Na_vβ1 contributes to the mechanism of epileptogenesis in these animals as well as in patients.