Autism-associated SCN2A deficiency disrupts cortico-striatal circuitry in human brain assembloids
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with SCN2A (voltage-gated sodium channel Na V 1.2) 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 observed in Scn2a +/- mice, highlighting a human-specific circuit vulnerability. Collectively, our study unveils human circuit-specific dysfunctions of SCN2A deficiency and SCN2A -mediated ASD.
Highlights
-
Axonal projections facilitate synapse formation and functional connectivity in human brain assembloids.
-
Na V 1.2 is expressed along neuronal axons, extending to soma and dendrites in human brain assembloids.
-
SCN2A-C959X disrupts axonal projection patterns, impairs excitatory synaptic transmission, reduces spine density, and results in elevated neuronal excitability.
In brief
SCN2A haploinsufficiency impairs cortico-striatal circuitry.
SCN2A haploinsufficiency disrupts axon initial segment (AIS) integrity, leading to hyperexcitability (red arrow), reduced axon projections, and impaired synaptic transmission (decreased sEPSCs and altered network firing). These deficits result in dysfunction within the cortico-striatal circuitry.
