DISC1 Pathway in Dendritogenesis: Implications for Dopamine Circuit and Cognition

树突发生中的 DISC1 通路：对多巴胺回路和认知的影响

• 批准号: 8101154
• 负责人: Atsushi Kamiya
• 金额: $ 32.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101154
• 关键词: Address; Animal Model; Binding; Brain; Cell Proliferation; Cell physiology; Cerebral cortex; Cognition; Data; Dendrites; Development; Disease; Disease susceptibility; Dopamine; Elements; Environmental Risk Factor; Etiology; Gene Expression; Gene Transfer; Genes; Genetic; Genetic Risk; Impaired cognition; Impairment; Injection of therapeutic agent; Lead; Mediating; Methods; Molecular; Mus; Neurons; Nuclear; Other Genetics; Pathology; Pathway interactions; Phenotype; Play; Prefrontal Cortex; Puberty; RNA Interference; Reporting; Risk; Role; Schizophrenia; Staging; System; Techniques; Testing; Virus Diseases; behavior test; cell behavior; cognitive function; genetic risk factor; immune activation; in utero; migration; mouse model; neurochemistry; neurodevelopment; overexpression; public health relevance; research study

DESCRIPTION (provided by applicant): Disturbances in neuronal circuit formation may underlie the pathology of schizophrenia. This notion is supported by the fact that many genetic risk factors for schizophrenia have roles in neurodevelopment. Some of them likely act in common molecular pathways, displaying synergistic effects on key phenotypes in neurodevelopment, such as dendritic development, in which abnormalities have been reported in schizophrenia. Furthermore, the interaction between genetic and environmental factors, such as viral infection, may play a role in the disease etiology. One example is the case of Disrupted-in-Schizophrenia-1 (DISC1), which plays a role in various cellular processes in the developing cerebral cortex by mediating interaction with other genetic risk factors, such as nuclear distribution element-like (NDEL1). To produce animal models in which the expression of multiple risk genes can be manipulated simultaneously, in utero gene transfer is a useful method. The feasibility of this technique for examining the effect of genetic insults on neuronal circuits and brain functions was confirmed by our preliminary data, which showed that knockdown of DISC1 in the developing prefrontal cortex (PFC) leads to the impairment of mesocortical dopaminergic maturation and cognition. Nonetheless, it is unclear which DISC1-mediated cell behaviors in the specific developmental period lead to these phenotypes. Thus, in this study, to examine the role of the DISC1 pathway in specific developmental periods, we will utilize in utero Cre/loxP-mediated inducible gene transfer system. We hypothesize that (1) inducible knockdown of DISC1 in post-migratory neurons (inducible DISC1 KD) in PFC may segregate a role for DISC1 in dendritogenesis, independent from the secondary effects of DISC1 in dendrites caused by disturbed cell proliferation and/or migration, which may be required for mesocortical dopamine maturation and proper cognitive functions, (2) DISC1-NDEL1 interaction may be necessary for dendritic development, as well as the establishment of dopamine circuit and cognition, and (3) virus infection in post-migratory stages may exacerbate the phenotypes displayed in inducible DISC1 KD mice. To address these hypotheses, first, we will examine the role of DISC1 on dendritic development, mesocortical dopamine maturation, and cognitive functions in mice in which DISC1 is selectively suppressed in post-migratory stages in PFC by in utero inducible RNAi transfer. Second, we will examine synergistic effects of DISC1 and NDEL1 on these phenotypes in which concomitant suppression of DISC1 and NDEL1 occurs in post-migratory stages. We will also examine DISC1-NDEL1 interaction by "rescue" experiments with overexpression of DISC1 lacking the NDEL1 binding domain. Finally, in order to test the combined effect of immune activation and inducible knockdown of DISC1, we will examine the effect of the injection of PolyI:C at post-migratory stages in inducible DISC1 KD mice. This study will be able to contribute to the identification of a genetic risk-mediated molecular pathway in the specific developmental periods which may lead to disease susceptibility. PUBLIC HEALTH RELEVANCE: The interaction between genetic risks and environmental factors, such as viral infection, during brain development, may play a role in the etiology of schizophrenia. In this study, we will explore a role for DISC1, a major genetic risk factor for schizophrenia, in the specific cellular process in brain development, which may be crucial for the establishment of dopamine maturation and cognitive functions. We will also examine combined effects of genetic disturbance of DISC1 and immune activation. This study will be able to contribute to the identification of genetic risk-mediated molecular pathway in the specific developmental periods which leads to disease susceptibility.

描述（由申请人提供）：神经元电路形成的干扰可能是精神分裂症病理学的基础。这一概念得到了以下事实的支持：许多精神分裂症的遗传危险因素在神经发育中具有作用。其中一些可能作用于共同的分子途径，对神经发育中的关键表型表现出协同作用，例如树突状发育，在精神分裂症中已经报道了异常。此外，遗传因素和环境因素（例如病毒感染）之间的相互作用可能在疾病病因中起作用。一个例子是中断中的schizizophrenia-1（Disc1），它通过与其他遗传危险因素（例如核分布元件样（NDEL1））进行介导相互作用，在发育中的大脑皮层中发挥了作用。为了产生动物模型，可以同时操纵多个风险基因的表达，在子宫基因转移中是一种有用的方法。我们的初步数据证实了该技术检查遗传损伤对神经元电路和大脑功能的影响的可行性，该数据表明，在发育中的前额叶皮层（PFC）中，DISC1的敲低导致心皮层多巴胺疗法成熟和认知受损。但是，尚不清楚在特定发育时期哪种盘状介导的细胞行为导致这些表型。因此，在这项研究中，为了检验Disc1途径在特定发育时期的作用，我们将在子宫/LOXP介导的诱导基因转移系统中使用。我们假设（1）PFC中氏二1次（可诱导的二张kd）中二张disc1的诱导型敲低可能会隔离二张盘在树突生成中的作用，而与二十二个二次效应在树突中的次级作用无关。相互作用对于树突状发育以及多巴胺回路和认知的建立可能是必需的，并且（3）迁移后阶段的病毒感染可能加剧了在诱导型二十二kD小鼠中显示的表型。首先，为了解决这些假设，我们将研究二氧化激素对树突状发育，中皮层多巴胺成熟和认知功能的作用，其中在子宫内诱导的RNAi转移中，disc1在PFC的术后阶段有选择地抑制了DISC1的作用。其次，我们将研究二氧化碳和NDEL1对这些表型的协同效应，在这些表型中，在移民后阶段会出现对Disc1和Ndel1的抑制作用。我们还将通过“拯救”实验进行盘状二型二号相互作用，而disc1的过表达缺乏NDEL1结合域。最后，为了测试免疫激活和disc1诱导型敲低的综合作用，我们将检查在诱导型二氧化碳1 kD小鼠中迁移后阶段注射polyi：c的作用。这项研究将能够为在特定发育时期的遗传风险介导的分子途径鉴定，这可能导致疾病的敏感性。 公共卫生相关性：遗传风险和环境因素（例如病毒感染）在大脑发育过程中的相互作用可能在精神分裂症的病因中起作用。在这项研究中，我们将探索精神分裂症的主要遗传危险因素Disc1在大脑发育的特定细胞过程中的作用，这对于建立多巴胺成熟和认知功能可能至关重要。我们还将检查椎间盘1和免疫激活的遗传障碍的综合作用。这项研究将能够在特定的发育期间鉴定遗传风险介导的分子途径，从而导致疾病的敏感性。