Chaodong Ding, Yiting Yuan, Yixin Hu, Yuefang Zhang, Shihao Wu, Ailian Du, Zilong Qiu
Pathogenic variants in ASXL3 underlie autism spectrum disorder (ASD), but how they perturb neural circuits and whether defects are reversible remain unclear. Here we show that Asxl3 haploinsufficiency in mice reduces cortical thickness and upper-layer projection neurons while increasing parvalbumin (PV) interneuron number and producing ASD-like behavioral abnormalities. Mechanistically, Asxl3 loss derepresses the thyroid hormone (TH)-inactivating enzyme DIO3 via altered histone H2A monoubiquitination, depleting brain TH. Conditional deletion of the TH receptor Thra in inhibitory neuron progenitors phenocopies the PV interneuron expansion, linking impaired TH signaling to PV circuit remodeling. Neonatal, but not adolescent, TH supplementation restores PV interneuron numbers and rescues behavior in Asxl3+/- mice, defining a critical early window for intervention. An intein-based AAV system that reconstitutes full-length ASXL3 normalizes cortical architecture and behavior in Asxl3+/- mice and drives efficient ASXL3 expression in non-human primate brain, establishing an ASXL3-TH-PV interneuron axis as a targetable pathway in ASD.