Title: CRISPRa-based rescue of sensorimotor deficits in the Scn2a+/- mouse model of autism
spectrum disorder
Project Summary: Heterozygous loss-of-function mutations in the sodium channel gene SCN2A
are strongly associated with autism spectrum disorder. SCN2A encodes the neuronal sodium
channel NaV1.2, which contributes to membrane excitability in somatodendritic or axonal
compartments, depending on cell class. Heterozygous loss of Scn2a, modeled in Scn2a+/- mice,
causes deficits in cellular excitability and synaptic function across multiple brain areas, and drives
robust systems- and behavioral-level deficits in sensory processing, neural coding, and
sensorimotor learning. Here, our goal is to rescue these cellular, circuit and behavioral deficits
using CRISPR-activation (CRISPRa)-based therapeutic approaches in Scn2a+/- mice.
Most autism risk genes, like SCN2A, are associated with autism by heterozygous loss-of-
function. CRISPRa is a promising therapeutic approach for many genetic forms of autism
because it upregulates expression of the remaining functional gene copy, potentially rescuing
cellular function. Scn2a+/- mice are an ideal test case for CRISPRa intervention in severe genetic
forms of autism.
We have developed CRISPRa-based reagents that restore Scn2a expression to near-
normal levels, and preliminary data show that treatment of adolescent Scn2a+/- mice with
CRISPRa successfully rescues cellular and synaptic phenotypes in at least one brain area. Here,
we will test the effectiveness of CRISPRa rescue of cellular, circuit, and behavioral phenotypes
across sensory, associative, and motor regions of the brain. To do so, we bring together three
laboratories with proven expertise in Scn2a disorders and autism, cellular and systems
physiology, and therapeutics. Results of this study will help establish the feasibility of gene
therapy for neurodevelopmental disorders including severe genetic forms of autism, and will help
define the critical developmental windows in which therapeutic interventions are most effective.