Autism is a neurodevelopmental disorder associated with deficits in social behaviors and characteristic repetitive behaviors. Gene profile analyses in autism have shown that a remarkable portion of autism- associated risk genes play a role in regulating myelination. SCN2A encodes the alpha subunit of the voltage-gated sodium channel 1.2 (Na_v1.2) and is a high-confidence autism risk gene.

The Na_v1.2 channel is expressed in both excitatory neurons and oligodendrocyte (OL) lineage cells, which are myelin-forming glial cells. Interestingly, Jun Hee Kim’s laboratory recently demonstrated that a subpopulation of immature pre-myelinating OLs expressing Na_v1.2 channels are capable of producing action potentials in the brainstem and that downregulation of Na_v1.2 expression in these OLs impairs myelination in the auditory brainstem¹. These data indicate a critical role for the Na_v1.2 channel in myelination. As both OL dysfunction and alterations in myelination have been shown to generate deficits in behaviors relevant to autism, including cognitive and social behaviors, Kim proposes that deficits in Na_v1.2-mediated oligodendroglial excitability could contribute to autism.

Kim hypothesizes that Na_v1.2-mediated excitability in developing OLs is required for coordinating neuron-OL interactions that underlie adaptive myelination and are essential for the proper development of neural circuits. She predicts that the absence of the Na_v1.2 channel in OLs alters myelination, resulting in impaired neurosensory signal transmission and altered cognitive function and social behaviors.

To test this hypothesis, Kim’s team has generated a novel Scn2a conditional knockout (cKO) mouse that lacks Scn2a specifically in OL cells. Electrophysiological recordings and dynamic Ca²⁺ imaging will be performed in these mice to investigate how Na_v1.2 expression in OLs contributes to myelination and circuit development. Aim one will determine the role of Na_v1.2 channels in OL development and myelination. Aim two will determine the role of Na_v1.2 channels in the physiological properties of OLs. Aim three will determine if the loss of oligodendroglial Na_v1.2 disrupts the proper development of neurosensory and social behaviors relevant to autism. The results are expected to provide novel insights into a potential mechanism by which Scn2a mutations cause autism and could lead to new potential therapeutic strategies for autism.