Portmann Thomas, Yang Mu, Mao Rong, Panagiotakos Georgia, Ellegood Jacob, Dolen Gul, Bader Patrick L, Grueter Brad A, Goold Carleton, Fisher Elaine, Clifford Katherine, Rengarajan Pavitra, Kalikhman David, Loureiro Darren, Saw Nay L, Zhengqui Zhou, Miller Michael A, Lerch Jason P, Henkelman Mark, Shamloo Mehrdad, Malenka Robert C, Crawley Jacqueline N, Dolmetsch Ricardo E
Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.
School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
Cell Rep. 2014 May 22;7(4):1077-1092. doi: 10.1016/j.celrep.2014.03.036. Epub 2014 May 1.
A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11(+/-)). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2(+)) and fewer dopamine-sensitive (Drd1(+)) neurons in deep layers of cortex. Electrophysiological recordings of Drd2(+) MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11(+/-) mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11(+/-) mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.
人类染色体16p11.2上的缺失与自闭症谱系障碍有关。我们删除了小鼠染色体7F3上的同区域。磁共振成像（MRI）和高通量单细胞转录组学揭示了解剖学和细胞异常，特别是在幼年突变小鼠（16p11(+/-)）的皮质和纹状体中。我们发现表达多巴胺D2受体（Drd2(+)）的纹状体中等棘状神经元（MSN）数量增加，而皮质深层中对多巴胺敏感（Drd1(+)）的神经元数量减少。对Drd2(+) MSN的电生理记录显示突触缺陷，表明16p11(+/-)小鼠的基底神经节回路功能异常。行为实验显示多动、转圈和运动控制缺陷，进一步支持了这一点。引人注目的是，16p11(+/-)小鼠表现出完全缺乏习惯化，这与在一些自闭症个体中观察到的情况相似。我们的研究结果揭示了受16p11.2缺失影响的基因在建立基底神经节回路中的基本作用，并为自闭症的病理生理学提供了见解。
