A NEW MOUSE MODEL OF NON-SYNDROMIC AUTISM SPECTRUM DISORDER CARRYING THE HUMAN NEGATIVE-DOMINANT MUTATION L1314P OF THE<EM> SCN2A/</EM>NA<SUB>V</SUB>1.2 SODIUM CHANNEL

Genetic variants in the SCN2A gene, encoding the voltage-gated sodium channel Na_V1.2, cause a spectrum of neurodevelopmental disorders with or without epilepsy. SCN2A loss of function (LOF) variants have been strongly associated with Autism Spectrum Disorder (ASD). Our functional studies show that SCN2A variants causing ASD without epilepsy (non-syndromic) induce negative dominant effects in vitro, resulting in a greater reduction of functional Na_V1.2 channels than that caused by pure LOF variants.
To date, mouse models of human SCN2A-ASD variants are lacking. We investigated behavioral and neuronal alterations in a novel heterozygous knock-in mouse carrying the L1314P negative-dominant mutation, identified in a patient with severe non-syndromic ASD, to explore mechanisms specific to ASD.
We assessed ASD-core features and comorbidities in Scn2a^L1314P/+ juvenile and adult male mice. To identify the underlying neuronal alterations, we performed patch-clamp recordings of prefrontal cortex (PFC) layer 5 pyramidal neurons across development. The molecular analysis included western blot and qPCR.
Scn2a^L1314P/+ male mice exhibit repetitive behaviors, hyporeactivity to aversive stimuli and altered decision-making, recapitulating some symptoms of ASD patients. Similar dysfunctions observed in adult mice suggest that this mutation causes enduring behavioral abnormalities in our model. This ASD-like phenotype is associated with impaired neuronal excitability in immature PFC pyramidal neurons. Molecular analysis revealed reduced Na_V1.2 membrane expression despite normal mRNA levels, suggesting folding or trafficking defects.
Our mouse model provides the first in vivo system for studying a human SCN2A-ASD variant to disclose ASD-specific pathological mechanisms and to develop targeted therapeutic strategies.