Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain
Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain
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DOI：
10.1016/j.cell.2007.07.010
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发表时间：
2007-09-21
期刊：
影响因子：
64.5
通讯作者：
Song, Hongjun
中科院分区：
文献类型：
--
作者：
Duan, Xin;Chang, Jay H.;Song, Hongjun
成人神经发生在成人哺乳动物大脑的离散区域中，贯穿一生。很少有人知道的机制，管理连续的发展过程，导致新的神经元从成人神经干细胞整合到现有的电路。在此，我们研究了精神分裂症易感基因DISC1在成年海马神经发生中的作用。出乎意料的是，DISC1的下调导致加速的神经元整合，导致异常的形态发育和新的齿状颗粒细胞以细胞自主的方式错位。在功能上，DISC1敲低的新生神经元表现出增强的兴奋性和加速的树突发育和突触形成。此外，DISC1与其结合伴侣NDEL1在调节成体神经发生中合作。综上所述，我们的研究确定DISC1作为一个关键的调节器，它协调了成年大脑中功能性神经元整合的节奏，并证明了易感基因在神经元发育（包括成年神经发生）中对重大精神疾病的重要作用。
Adult neurogenesis occurs throughout life in discrete regions of the adultmammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted- In- Schizophrenia 1 ( DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell- autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.