Autism-associated <i>SCN2A</i> deficiency disrupts cortico-striatal circuitry in human brain assembloids.

ABSTRACT: Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with SCN2A (voltage-gated sodium channel Na_V1.2) protein-truncating variants (PTVs) being one of the most penetrant. Although cortico-striatal circuitry is implicated as a key node in ASD, the impact of SCN2A deficiency on human neural circuits is unknown. Using the human cortico-striatal assembloid model, we show that the autism-causing PTV SCN2A-C959X impairs long-range cortical axonal projections, reduces striatal spine density, and attenuates excitatory cortical-striatal synaptic transmission. Surprisingly, these assembloids carrying the heterozygous SCN2A nonsense mutation exhibited pronounced network hyperexcitability, a human cell-specific phenotype not

SUBMITTER: Chen X 

PROVIDER: S-EPMC12157400 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature