Selective loss of Scn2a in ventral tegmental area dopaminergic neurons leads to dopamine system hypofunction and autistic-like behaviors.

Dopamine hypothesis has been proposed as a mechanism of autism spectrum disorder (ASD), a neurodevelopmental disorder closely associated with genetic mutations. Loss-of-function mutation of SCN2A, which encodes the voltage-gated Na⁺ channel Na_V1.2, is a high risk factor for autism, but whether its pathogenesis is attributable to dopamine system dysfunction remains unclear. Here, we found that Scn2a is the predominant isoform and contributes largely to Na⁺ currents along the somato-axonal axis of dopaminergic neurons (DANs) in mouse ventral tegmental area (VTA). Complete deletion of Scn2a in VTA DANs reduces their spiking activity and dopamine release, leading to hyperactivity, impaired sociability, and insufficient anxiety. Similar alterations were observed in Scn2a heterozygous mice. Importantly, acute treatment with levodopa alleviates non-motor behavior deficits. Together, the results reveal that Scn2a loss in VTA DANs alone causes autistic-like behaviors through a dopamine-hypofunction mechanism and also provide a possible pharmacotherapy through dopamine replacement for ASD with SCN2A mutations.