Immune molecules in early postnatal nervous system development

描述(由申请人提供)：尽管多年来免疫系统和神经系统之间存在相互作用的证据，但免疫分子在正常发育的神经系统中具有非免疫功能的想法直到最近才得到信任。这个想法是基于对适应性免疫反应的主要介质-主要组织相容性复合体I类(MHCI)分子-在大脑中表达的观察，在那里它们介导了依赖活动的连接的细化。MHCI分子也是异常或强烈免疫反应对发育中大脑影响的分子介体，这与包括自闭症和精神分裂症在内的几种神经发育障碍的发病机制有关。这项建议的中心目标是确定MHCI在皮质连接的初始建立过程中的功能，这是一个与免疫挑战时间相当的发育阶段，免疫挑战可能使人类倾向于神经发育障碍。利用免疫细胞和组织化学、电子显微镜、细胞和切片培养和转染法、一种新的长期成像分析方法和全细胞膜片钳记录，我们将解决以下目标。(1)研究大脑皮质发育过程中MHCI分子在体内和体外的定位。(2)验证MHCI分子在体内和体外调节皮质连接的初始建立和功能的假说。(3)确定MHCI分子是否通过抑制突触形成、增加突触消除或两者兼而有之来负向调节皮质连接的建立。(4)验证MHCI分子通过自然杀伤细胞受体负性调节皮质连接建立的假说。这一提议的结果应该揭示MHCI在典型发育中的大脑中的新功能，以及它们可能如何贡献的潜在机制 神经发育障碍。 与公共健康相关：虽然已经提出了广泛的环境刺激在包括自闭症和精神分裂症在内的神经发育障碍的发病机制中发挥作用，但这些刺激中的许多都具有改变免疫功能的共同能力。由于MHCI分子启动和介导免疫反应9，并存在于大脑10中，因此完全有可能是环境侮辱引起的发育中大脑MHCI表达的变化促成了导致这些疾病的细胞变化。这项提议的中心目标是确定MHCI蛋白在出生后早期大脑连接的初始形成过程中的功能，这是一个与免疫挑战时期相当的发育阶段，免疫挑战的提出使人类容易患上神经发育障碍。

DESCRIPTION (provided by applicant): Although there has been evidence for cross-talk between the immune and nervous systems for years, the idea that immune molecules have non-immune functions in the normal developing nervous system has only recently gained credence. This idea is based on observations that the primary mediators of the adaptive immune response, major histocompatibility complex class I (MHCI) molecules, are expressed in the brain where they mediate activity-dependent refinement of connections. MHCI molecules are also attractive candidates for molecular mediators of the effects of an abnormal or strong immune response on the developing brain, which has been implicated in the pathogenesis of several neurodevelopmental disorders, including autism and schizophrenia. The central goal of this proposal is to determine the function of MHCI during the initial establishment of cortical connections, a comparable developmental stage to the time of the immune challenge that may predispose humans toward neurodevelopmental disorders. Using immunocyto- and histochemistry, electron microscopy, cell and slice culture and transfection, a novel long-term imaging assay, and whole-cell patch-clamp recording, we will address the following Aims. (1) To determine the localization of MHCI molecules in vivo and in vitro during cortical development. (2) To test the hypothesis that MHCI molecules regulate the initial establishment and function of cortical connections in vivo and in vitro. (3) To determine whether MHCI molecules negatively regulate the establishment of cortical connections by inhibiting synapse formation, increasing synapse elimination, or both. (4) To test the hypothesis that MHCI molecules act through natural killer cell receptors to negatively regulate the establishment of cortical connections. Results from this proposal should reveal novel functions of MHCI in the typically developing brain, as well as potential mechanisms for how they might contribute to neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Although a wide range of environmental stimuli have been proposed to play a role in the pathogenesis of neurodevelopmental disorders including autism and schizophrenia, many of these stimuli have in common the ability to alter immune function. Since MHCI molecules initiate and mediate the immune response 9 and are present in the brain 10, it is entirely possible that changes in expression of MHCI in the developing brain caused by environmental insults contribute to the cellular changes that cause these disorders. The central goal of this proposal is to determine the function of MHCI proteins during the initial formation of connections in the early postnatal brain, a comparable developmental stage to the time of the immune challenge proposed to predispose humans toward neurodevelopmental disorders.