Li Weidong, Zhou Yu, Jentsch J David, Brown Robert A M, Tian Xiaoli, Ehninger Dan, Hennah William, Peltonen Leena, Lönnqvist Jouko, Huttunen Matti O, Kaprio Jaakko, Trachtenberg Joshua T, Silva Alcino J, Cannon Tyrone D
Department of Neurobiology, Semel Institute, Brain Research Institute, and Department of Urology, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18280-5. doi: 10.1073/pnas.0706900104. Epub 2007 Nov 2.
Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.
精神分裂症断裂基因1（DISC1）最初是通过一个平衡易位（1；11）（q42.1；q14.3）发现的，该易位导致DISC1蛋白C端缺失，该区域被认为在大脑发育中起重要作用。在此，我们使用一种诱导性和可逆性转基因系统来证明，在小鼠出生后早期而非成年期诱导DISC1的C端部分会导致一系列与精神分裂症相关的表型，包括海马树突复杂性降低、抑郁样特征、异常的空间工作记忆和社交能力下降。因此，我们报告称，在一个不一致的双胞胎样本中，携带与精神分裂症以及工作记忆损害和灰质密度降低相关的DISC1单倍型的个体比没有该单倍型的个体更有可能表现出社交能力缺陷。我们的研究结果表明，大脑发育过程中DISC1功能的改变有助于精神分裂症的发病机制。
