Sh3rf2 Haploinsufficiency Leads to Unilateral Neuronal Development Deficits and Autistic-Like Behaviors in Mice
Sh3rf2 Haploinsufficiency Leads to Unilateral Neuronal Development Deficits and Autistic-Like Behaviors in Mice
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Sh3rf2 单倍体不足导致小鼠单侧神经元发育缺陷和自闭症样行为。
DOI：
10.1016/j.celrep.2018.11.044
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发表时间：
2018-12-11
期刊：
影响因子：
8.8
通讯作者：
Xu, Zhiheng
中科院分区：
文献类型：
--
作者：
Wang, Shuo;Tan, Ningdong;Xu, Zhiheng
自闭症谱系障碍（ASDs）包括多种发育性脑障碍，临床发现涉及左半球功能障碍。在这里，我们培养了缺乏ASD患者中检测到的Sh3rf2拷贝的小鼠，以确定Sh3rf2是否参与大脑发育，Sh3rf2突变是否导致ASD及其与ASD特征相关的机制。我们发现，Sh3rf2单倍功能不全的小鼠在社交和交流方面表现出明显的缺陷，以及刻板或重复的行为、多动和癫痫发作。在杂合突变体中检测到海马树突棘发育紊乱，谷氨酸能受体亚基组成异常，兴奋性突触传递异常。值得注意的是，这些缺陷是选择性单侧的。我们的研究结果支持了一个观点，即Sh3rf2单倍性不足是ASD的一个高度渗透的危险因素，疾病的发病机制很可能是由大脑左半球突触功能缺陷引起的。
Autism spectrum disorders (ASDs) include a variety of developmental brain disorders with clinical findings implicating the dysfunction of the left hemisphere. Here, we generate mice lacking one copy of Sh3rf2, which was detected in ASD patients, to determine whether Sh3rf2 is involved in brain development and whether mutation of SH3RF2 is causative for ASD and the mechanisms linking it to ASD traits. We find that mice with Sh3rf2 haploinsufficiency display significant deficits in social interaction and communication, as well as stereotyped or repetitive behaviors and hyperactivity and seizures. Disturbances in hippocampal dendritic spine development, aberrant composition of glutamatergic receptor subunits, and abnormal excitatory synaptic transmission were detected in heterozygous mutants. Remarkably, these defects are selectively unilateral. Our results support a notion that Sh3rf2 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis most likely resulting from deficits in synaptic function in the left hemisphere of the brain.