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 (Nav1.2) and is a high-confidence autism risk gene.
The Nav1.2 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 Nav1.2 channels are capable of producing action potentials in the brainstem and that downregulation of Nav1.2 expression in these OLs impairs myelination in the auditory brainstem1. These data indicate a critical role for the Nav1.2 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 Nav1.2-mediated oligodendroglial excitability could contribute to autism.
Kim hypothesizes that Nav1.2-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 Nav1.2 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 Nav1.2 expression in OLs contributes to myelination and circuit development. Aim one will determine the role of Nav1.2 channels in OL development and myelination. Aim two will determine the role of Nav1.2 channels in the physiological properties of OLs. Aim three will determine if the loss of oligodendroglial Nav1.2 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.
- Cellular and circuit effects of SCN2A haploinsufficiency
- Electrophysiological consequences of SCN2A mutations found in autism
- SCN2A mouse
- Development of CRISPR activation therapeutics to rescue SCN2A function
- In vivo calcium dynamics in dendritic spines of Shank3 and Scn2a mutant mouse models of autism
- Myelin integrity and plasticity in a neuroligin 3 mouse model of autism