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Sodium channel dysfunction in autism spectrum disorder

  • Author(s): Spratt, Perry William Eric
  • Advisor(s): Nelson, Alexandra
  • et al.
Abstract

Dysfunction in the gene SCN2A has a strong association with autism spectrum disorder (ASD). SCN2A encodes the protein NaV1.2, a voltage-gated sodium channel important for the initiation and propagation of action potential in excitatory neurons in the developing cortex. ASD-associated SCN2A variants impair the function of NaV1.2, however, the resulting consequences of NaV1.2 dysfunction for ASD are unknown. In this dissertation, I show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons, in addition to regulating axonal excitability early in development. Scn2a-haploinsufficiency disrupts action potential propagation into the dendritic arbor, impairing synaptic plasticity and function, even when NaV1.2 expression is disrupted in a cell-autonomous fashion late in development. Homozygous Scn2a-loss further exacerbates dendritic excitability deficits, yet paradoxically increases axonal excitability, likely resulting from compensation by other sodium channel genes. Encouragingly, restoring Scn2a expression in mature neurons appears sufficient to rescue dendritic and synaptic impairments. CRISPR activators are demonstrated as a variable approach for exogenously increasing Scn2a expression, restoring dendritic excitability and synaptic function in Scn2a-haploinsufficient mice. Overall, these results reveal a novel dendritic function for NaV1.2, provide insight into cellular mechanisms underlying circuit and behavioral dysfunction in ASD, and identify potential therapeutic avenues for loss-of-function SCN2A cases and other haploinsufficient ASD genes.

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