Na v igating Phenotypic Characterization and CRISPRa Restoration for SCN2A Haploinsufficiency Disorders
Year: 2026
Type: editorial
Abstract: Sex-Specific Behavioral Features of Juvenile and Adult Haploinsufficient Scn2a +/− Female Mice, Model of Autism Spectrum Disorder Marcantonio W, Simonti M, Lena I, Mantegazza M. Genes Brain Behav. 2025;24(5):e70034. Genetic variants of the SCN2A gene, encoding the Na V 1.2 sodium channel, cause a spectrum of neurodevelopmental and epileptic disorders, and are among those that show the strongest association with Autism Spectrum Disorder (ASD). ASD has a male-bias prevalence, but several studies have proposed that female prevalence may be underestimated due to different symptomatic expression compared with males. However, it is unclear whether this is related to actual different pathological features or to greater masking abilities in females. Studies on Scn2a +/− mice, a model of SCN2A haploinsufficiency and ASD, have shown an age-dependent ASD-like phenotype attenuated at adulthood in males. However, little is known about the behavioral features of Scn2a +/− female mice. We performed a battery of behavioral tests that are relevant for assessing ASD-like features, investigating juvenile and adult Scn2a +/− female mice. Our results demonstrate that female Scn2a +/− mice exhibit an overall milder phenotype than males, showing increased risk-taking in juveniles, hyper-reactivity to cold stimuli, and mild memory impairments in adults, abnormally increased sociability, and altered decision-making related behaviors in both juveniles and adults. Thus, this aligns with the male-biased prevalence of ASD and supports the existence of sex-specific phenotypic differences, potentially arising from distinct underlying pathophysiological mechanisms. Both sexes should be investigated in studies of mouse models of ASD. CRISPR Activation for SCN2A -Related Neurodevelopmental Disorders Tamura S, Nelson AD, Spratt PW, Hamada EC, Zhou X, Kyoung H, Li Z, Arnould C, Barskyi V, Krupkin B, Young K. Nature , 2025;646, 983–991. Most neurodevelopmental disorders with single gene diagnoses act via haploinsufficiency, in which only one of the two gene copies is functional. SCN2A haploinsufficiency is one of the most frequent causes of neurodevelopmental disorder, often presenting with autism spectrum disorder, intellectual disability, and, in a subset of children, refractory epilepsy. Here, using SCN2A haploinsufficiency as a proof-of-concept, we show that upregulation of the existing functional gene copy through CRISPR activation (CRISPRa) can rescue neurological-associated phenotypes in Scn2a haploinsufficient mice. We first show that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency ( Scn2a +/− ). Next, using an adeno-associated virus CRISPRa-based treatment in adolescent mice, we show that we can correct intrinsic and synaptic deficits in neocortical pyramidal cells, a major cell type that contributes to neurodevelopmental disorders and seizure aetiology in SCN2A haploinsufficiency. Furthermore, we find that systemic delivery of CRISPRa protects Scn2a +/− mice against chemoconvulsant-induced seizures. Finally, we also show that adeno-associated virus CRISPRa treatment rescues excitability in SCN2A haploinsufficient human stem-cell-derived neurons. Our results showcase the potential of this therapeutic approach to rescue SCN2A haploinsufficiency and demonstrates that rescue even at adolescent stages can ameliorate neurodevelopmental phenotypes.
Author: Jennifer C. Wong
Institution: Emory University
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7118190679