Autism-associated deficiency disrupts cortico-striatal circuitry in human brain assembloids.

Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with (voltage-gated sodium channel Na1.2) 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 deficiency on human neural circuits is unknown. Using the human cortico-striatal assembloid model, we show that the autism-causing PTV impairs long-range cortical axonal projections, reduces striatal spine density, and attenuates excitatory cortical-striatal synaptic transmission. Surprisingly, these assembloids carrying the heterozygous nonsense mutation exhibited pronounced network hyperexcitability, a human cell-specific phenotype not observed in mice, highlighting a human-specific circuit vulnerability. Collectively, our study unveils human circuit-specific dysfunctions of deficiency and -mediated ASD.