CRISPRa-based rescue of sensorimotor deficits in the Scn2a+/- mouse model of autism spectrum disorder

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.