RESTORING THE CLOCK: CIRCADIAN RHYTHM MODULATION AS A NOVEL THERAPY FOR SCN2A-ASSOCIATED AUTISM SPECTRUM DISORDER

The voltage-gated sodium channel Na_V1.2, encoded by SCN2A, is highly expressed at the axon initial segment of neurons, where it plays a critical role in action potential initiation and backpropagation. Pathogenic SCN2A variants are a major cause of neurodevelopmental disorders, including autism spectrum disorder (ASD) and developmental and epileptic encephalopathy (DEE). The biophysical consequences of these variants—gain-of-function (GoF), loss-of-function (LoF), or mixed GoF/LoF—closely correlate with disease severity. Notably, individuals carrying LoF or mixed GoF/LoF variants frequently exhibit profound sleep disturbances, suggesting that Na_V1.2 dysfunction directly disrupts circadian regulation and exacerbates neurodevelopmental phenotypes. Here, we investigate whether circadian dysregulation contributes to cognitive and behavioral impairments in SCN2A-related disorders and whether restoring circadian function can ameliorate these deficits. We focus on the recurrent SCN2A R853Q mutation, which produces a mixed GoF/LoF phenotype by inducing a pathological gating pore current while reducing transient sodium current. We generated a knock-in mouse model harboring the orthologous Na_V1.2(R854Q) mutation, which recapitulates key ASD phenotypes, including social and communication deficits, repetitive behaviors and cognitive impairments. RNA sequencing of hippocampal tissue revealed downregulation of core circadian genes, indicating intrinsic circadian disruption. We are currently characterizing sleep–wake behavior and assessing diurnal gene expression in the hippocampus of Na_V1.2(R854Q) mice. In parallel, we are evaluating whether melatonin treatment can normalize circadian rhythms and ameliorate behavioral, cognitive, and synaptic alterations. Together, these ongoing studies aim to define circadian disruption as a mechanistic contributor to SCN2A-related neurodevelopmental disorders and to explore circadian restoration as a potential therapeutic strategy.