Chen Xiaoling, Zhang Jingliang, Wu Jiaxiang, Robinson Morgan J, Kothandaraman Harish, Yoo Ye-Eun, Dopeso-Reyes Iria M Gonzalez, Buffenoir Thomas D, Halurkar Manasi S, Zhang Zaiyang, Wang Muhan, Creager Erin N, Zhao Yuanrui, Olivero-Acosta Maria I, Wettschurack Kyle W, Que Zhefu, Yuan Chongli, Schaser Allison J, Lanman Nadia A, Rochet Jean-Christophe, Skarnes William C, Kremer Eric J, Yang Yang
Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA.
bioRxiv. 2025 Jun 3:2025.06.02.657036. doi: 10.1101/2025.06.02.657036.
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.
重度自闭症谱系障碍（ASD）通常归因于单基因突变，其中（电压门控钠通道Na1.2）蛋白截短变体（PTV）是最具外显率的突变之一。尽管皮质-纹状体回路被认为是ASD的关键节点，但Na1.2缺乏对人类神经回路的影响尚不清楚。利用人类皮质-纹状体组装体模型，我们发现导致自闭症的PTV损害长距离皮质轴突投射，降低纹状体棘密度，并减弱兴奋性皮质-纹状体突触传递。令人惊讶的是，携带杂合Na1.2无义突变的这些组装体表现出明显的网络过度兴奋，这是在Na1.2基因敲除小鼠中未观察到的人类细胞特异性表型，突出了人类特异性的回路易损性。总之，我们的研究揭示了Na1.2缺乏和Na1.2介导型ASD的人类回路特异性功能障碍。
