Degraded sensory coding in a mouse model of Scn2a-related disorder and its rescue by CRISPRa gene activation.

Heterozygous loss-of-function mutations in SCN2A, a sodium channel gene expressed in cortical pyramidal (PYR) cells, lead to a neurodevelopmental disorder characterized by autism, intellectual disability, and cortical sensory dysfunction. In Scn2a+/- mice, PYR dendritic excitability and synapses are impaired, but cortical information processing deficits are unknown. In the whisker somatosensory cortex, we found strongly degraded somatotopic tuning of PYR cells, profoundly blurred whisker maps, and impaired population coding, despite normal overall firing rates. This constitutes a robust biomarker for Scn2a-related cortical dysfunction. Parvalbumin (PV) interneurons were also unexpectedly hypofunctional. We tested for rescue of coding deficits in post-critical period, young adult mice by viral delivery of CRISPR activation (CRISPRa) reagents that upregulate Scn2a. CRISPRa treatment normalized cortical sensory representations at the single-unit and map levels. This suggests that therapy to increase Scn2a expression may be effective in normalizing cortical function in Scn2a loss-of-function disorder, even in older children or adults.