Project 3

精神分裂症领域最近的一个令人兴奋的发现是多个易感基因的鉴定 人类遗传学研究的成果最近的研究也加强了一种新的观点，即精神分裂症 是一种成年人发病的神经元发育疾病。精神分裂症的易感性 然而，基因调节神经元发育的不同方面在很大程度上是未知的。海马 和海马神经发生与精神分裂症和抑郁症密切相关， 许多抗抑郁药的治疗作用。在海马体中，齿状回中的颗粒细胞是 在包括人类在内的所有哺乳动物的一生中，神经祖细胞持续产生。 它们遵循神经元形态发生、迁移、轴突和树突靶向以及 在出生后一个月内成为突触整合到现有的神经元回路中。如此刻板 和延长的神经元发育的一个单一的CMS神经元亚型在一个相对稳定的状态成熟 中枢神经系统环境提供了一个独特的机会，研究神经元的分子和细胞机制， 体内发育我们开发了一种逆转录病毒介导的“单细胞遗传”方法来研究 新生颗粒细胞在体内脑中的发育， 免疫细胞化学、多光子共聚焦显微镜、电子显微镜和电生理学。使用 这些方法，我们最近研究了分裂症1（DISC1）的功能， 精神分裂症易感基因，并表明DISC1调节神经元发育的多个阶段 颗粒细胞在体内。在目前的项目中，我们的目标是扩展这些初步发现，并描述 DISC1与其相互作用物，如NDEL1和FEZ1，在调节 体内神经发生和神经元发育。我们还将研究是否有缺陷的神经发生， DISC1功能障碍会导致动物行为的改变。此外，我们将确定分子 DISC1在神经发生和神经元发育中的潜在机制。我们还将研究 DISC1功能障碍导致的神经发生缺陷将导致动物行为的改变。我们设想我们的 这项研究将填补我们对精神分裂症易感基因功能的基础知识的差距， 神经元的发育，并可能揭示精神分裂症的病因和发病机制。

One of the recent excitements in the schizophrenia field is the identification of multiple susceptibility genes from human genetic association studies. Recent studies also reinforce the emerging view that schizophrenia is a disease of neuronal development in nature with an adult onset. How specific schizophrenia susceptibility genes regulate different aspects of neuronal development, however, is largely unknown. The hippocampus and hippocampal neurogenesis are stronly implicated in schizophrenia and depression, and in the therapeutic actions of many anti-depressants. Within the hippocampus, granule cells in the dentate gyrus are continuously generated from neural progenitors throughout life in all mammals examined, including humans. They follow stereotypic patterns of neuronal morphogenesis, migration, axon and dendritic targeting and become synaptic integrated into the exiting neuronal circuits within one month after birth. Such stereotypic and prolonged neuronal development of a single CMS neuronal subtype in a relative steady-state of mature CNS environment offers a unique opportunity to investigate molecular and cellular mechanisms of neuronal development in vivo. We have developed a retrovirus-mediated "single-cell genetic" approach for study of the development of newborn granule cells in the brain in vivo using a combinational approach of immunocytochemistry, multiphoton confocal microscopy, electron microscopy and electrophysiology. Using these approaches, we have recently examined the function of Disrupted-in-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, and shown that DISC1 regulates multiple phases of neuronal development of granule cells in vivo. In the current project, we aim to extent these preliminary findings and characterize the functions of DISC1 in conjunction with its interactors, such as NDEL1 and FEZ1, in regulating neurogenesis and neuronal development in vivo. We will also examine whether defects of neurogenesis from DISC1 dysfunction will lead to changes in animal behaviors. Furthermore, we will determine the molecular mechanisms underlying DISC1 in neurogenesis and neuronal development. We will also examine whether defects of neurogenesis from DISC1 dysfunction will lead to changes in animal behaviors. We envision our study will fill the gap of our basic knowledge about the functions of schizophrenia susceptibility genes in neuronal development and may reveal the etiology and pathogenesis of schizophrenia.