- SCN2A PTVs impair long-range cortical axonal projections, reduce striatal spine density and weaken excitatory cortico-striatal synaptic transmission.
- Both impaired cortical projections and intrinsic striatal vulnerability contribute to genotype-specific circuit deficits in assembloid models.
- Despite connectivity deficits, SCN2A-deficient neurons are hyperexcitable and assembloids show elevated spontaneous firing; canine adenovirus-mediated human SCN2A rescues deficits.
Neuron. 2026 Sep 30:S0896-6273(26)00682-3. doi: 10.1016/j.neuron.2026.08.031. Online ahead of print.
ABSTRACT
Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with SCN2A, encoding the voltage-gated sodium channel NaV1.2, among the most penetrant. Cortico-striatal circuitry is a key node implicated in ASD, yet how SCN2A deficiency alters human neural circuits remains unclear. Using a human cortico-striatal assembloid model, we show that autism-causing heterozygous SCN2A protein-truncating variants (PTVs) impair long-range cortical axonal projections, reduce striatal spine density, and attenuate excitatory cortico-striatal synaptic transmission. Genotype-defined assembloids reveal contributions from both impaired cortical projections and intrinsic striatal vulnerability. Paradoxically, despite these connectivity deficits, SCN2A-deficient neurons exhibit increased intrinsic excitability, and assembloids show elevated spontaneous network firing, suggesting a potentially distinctive feature of human neural models. Notably, canine adenovirus type 2-mediated delivery of human SCN2A rescued cellular and circuit deficits. Collectively, our study unveils human circuit dysfunction caused by SCN2A deficiency and supports the therapeutic potential of targeted gene replacement for SCN2A-related ASD.
PMID:42815470 | DOI:10.1016/j.neuron.2026.08.031
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