SCN2A contributes to oligodendroglia excitability and development in the mammalian brain

Spiking immature oligodendrocytes (OLs), referred to as spiking OLs, express voltage-activated Na⁺ channels (Na_v) and K⁺ (K_v) channels, endowing a subpopulation of OLs with the ability to generate Na_v-driven spikes. In this study, we investigate the molecular profile of spiking OLs, using single-cell transcriptomics paired with whole-cell patch-clamp recordings. SCN2A, which encodes the channel Na_v1.2, is specifically expressed in spiking OLs in the brainstem and cerebellum, both in mice and in Olive baboons. Spiking OLs express lineage markers of OL progenitor cells (OPCs) and pre-myelinating OLs, indicating they belong to a transitional stage during differentiation. Deletion of SCN2A reduces the Na_v current-expressing OL population and eliminates spiking OLs, indicating that SCN2A is essential for spiking in OLs. Deletion of SCN2A does not impact global OL proliferation but disrupts maturation of a subpopulation of OLs, suggesting that Na_v1.2 is involved in heterogeneity in OL lineage cells and their development.