Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse
Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse
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DOI：
10.1093/hmg/ddr400
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Kaibuchi, Kozo
中科院分区：
文献类型：
--
作者：
Kuroda, Keisuke;Yamada, Shinnosuke;Kaibuchi, Kozo
DISC 1基因是一个很有前途的候选基因，与精神疾病（包括精神分裂症）的易感性有关。DISC 1似乎参与神经发生、神经元迁移、轴突/树突形成和突触形成;在这些过程中，DISC 1通过与各种伙伴相互作用而充当支架蛋白。然而，缺乏Disc 1基因敲除小鼠和一个良好的表征抗体DISC 1已经很难确定DISC 1在体内的确切作用。在这项研究中，我们产生的小鼠缺乏外显子2和3的DISC 1基因和制备特异性抗体的N-和C-末端的DISC 1。Disc 1突变小鼠是可行的和可生育的，没有观察到的总表型，如脑细胞结构的紊乱。Western印迹分析显示，DISC 1特异性抗体识别野生型小鼠脑提取物中表观分子量类似于100 kDa的蛋白质，但不识别DISC 1突变小鼠脑提取物中的蛋白质。免疫组化研究表明DISC 1主要定位于海马神经元和星形胶质细胞的高尔基体附近。全长Disc 1的缺陷引起的阈值偏移在齿状回的长时程增强的诱导。通过高架十字迷宫和悬崖回避测试评估，Disc 1突变小鼠表现出异常的情绪行为，从而表明全长DISC 1的缺乏可能导致较低的焦虑和/或较高的冲动。基于这些结果，我们认为全长DISC 1缺陷小鼠和DISC 1特异性抗体是解剖DISC 1的病理生理功能的有力工具。
Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of Disc1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. In this study, we generated mice lacking exons 2 and 3 of the Disc1 gene and prepared specific antibodies to the N-and C-termini of DISC1. The Disc1 mutant mice are viable and fertile, and no gross phenotypes, such as disorganization of the brain's cytoarchitecture, were observed. Western blot analysis revealed that the DISC1-specific antibodies recognize a protein with an apparent molecular mass of similar to 100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. Immunochemical studies demonstrated that DISC1 is mainly localized to the vicinity of the Golgi apparatus in hippocampal neurons and astrocytes. A deficiency of full-length Disc1 induced a threshold shift in the induction of long-term potentiation in the dentate gyrus. The Disc1 mutant mice displayed abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. Based on these results, we suggest that full-length Disc1-deficient mice and DISC1-specific antibodies are powerful tools for dissecting the pathophysiological functions of DISC1.