Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory.
Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory.
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DOI：
10.1371/journal.pone.0145979
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hoshino M
中科院分区：
文献类型：
--
作者：
Hori K;Nagai T;Shan W;Sakamoto A;Abe M;Yamazaki M;Sakimura K;Yamada K;Hoshino M
自闭症易感性候选基因2 （AUTS2）的突变与一系列精神疾病有关，包括自闭症谱系障碍、智力残疾和精神分裂症。我们之前证明了细胞质AUTS2作为Rho家族小GTPase Rac1和Cdc42的上游因子，调节神经细胞的细胞骨架重排。此外，小鼠中Auts2基因的基因消融导致rac1信号通路失活导致发育中的大脑皮层神经元迁移和神经发生缺陷，这表明Auts2是神经发育所必需的。在这项研究中，我们对Auts2杂合突变小鼠进行了一系列行为分析，以研究Auts2在成人认知脑功能中的作用。在没有任何运动功能障碍的情况下，缺乏auts2的小鼠表现出探索行为的减少以及焦虑样行为的减少。此外，Auts2突变小鼠的新物体识别能力和线索联想记忆能力受损。然而，通过三室试验和脉冲前抑制试验评估，突变小鼠的社会行为和感觉运动门控功能正常。总之，我们的研究结果表明，AUTS2对神经认知功能的习得至关重要。
Mutations in the Autism susceptibility candidate 2 gene (AUTS2) have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.