New components of a molecular program for experience–dependent neural circuit refinement

 描述（由申请人提供）：成人神经系统必须完成各种各样的功能，包括处理环境刺激，如光、声音和气味，产生运动和学习，以及调节稳态。在发育过程中，神经元必须连接到精确的神经网络中，以驱动这些复杂的行为。最初，神经元建立非常精确的连接并建立粗略的组织水平，然后根据神经活动在数量和强度上细化这些连接。活动依赖性机制对于发育中的大脑成熟是必不可少的，并且最近被认为是几种神经精神障碍（包括精神分裂症和自闭症谱系障碍）的病理生理学的分子基础。这项提议的主要目标是确定分子程序的组成部分，通过这些分子程序，活动可以改善发育中的神经回路。 Shatz实验室的研究发现，主要组织相容性复合物I类（MHCI）蛋白在神经网络的活动依赖性细化中发挥着令人惊讶的作用。在神经元中观察到MHCI表达是出乎意料的，因为大脑在历史上被认为是免疫豁免的环境，并且MHCI分子的公认功能是在免疫系统中，其中它们参与识别自身与外来物。神经元中MHCI的存在是另外值得注意的，因为在全基因组关联研究中，MHC基因组簇中的多态性与几种神经精神疾病相关，并且事实上MHC基因座与精神分裂症具有最强的关联。Shatz实验室进一步揭示了两个经典的MHCI基因（H-2Db和H-2Kb）受活动调节，并且是突触修剪所必需的，突触修剪可以改善发育中视觉系统的初始连接。然而，有超过50个MHCI基因，但迄今为止，只有这两个在大脑中进行了研究。 我在这里提出的初步数据，一个非经典的MHCI，Qa-1，这还没有被检查在神经系统中，是由视觉皮层的神经元表达。在免疫系统中，Qa-1与H-2Db和H-2Kb不同的受体（CD 94/NKG 2）相互作用。我还提出了初步的数据，Qa- 1的同源受体，CD 94/NKG 2s的组件，也由神经元表达。该建议的中心目标是使用遗传学，组织学，电生理学和生物化学技术，以阐明功能的Qa-1及其受体在突触修剪和可塑性发育过程中使用视觉系统作为模型。我将专门测试的假设，Qa-1是一个组成部分的途径，执行活动依赖性的变化，在神经网络，并通过与不同的受体比经典的MHCIs，Qa-1在这个发展过程中发挥独特的功能。这项研究的长期目标是有助于我们理解神经发育障碍的病理生理学的分子基础。

 DESCRIPTION (provided by applicant): The adult nervous system must accomplish a vast variety of functions including processing environmental stimuli such as light, sounds, and odors, generating motion and learning, and regulating homeostasis. During development, neurons must wire into precise neural networks in order to drive these complex behaviors. Initially, neurons make grossly accurate connections and establish a coarse level of organization, and then these connections are refined in both number and strength based on neural activity. Activity-dependent mechanisms are essential for the developing brain to mature and have recently been implicated as a molecular basis for the pathophysiology of several neuropsychiatric disorders, including schizophrenia and autism spectrum disorders. The major goal of this proposal is to identify components of the molecular program by which activity refines developing neural circuits. Research in the Shatz lab discovered a surprising role for major histocompatibility complex class I (MHCI) proteins in activity-dependent refinement of neural networks. Observation of MHCI expression in neurons was unexpected because the brain had historically been considered an immunoprivileged environment and the well-established function of MHCI molecules is in the immune system where they are involved in the recognition of self versus foreign. The presence of MHCIs in neurons is additionally notable because in genome-wide association studies, polymorphisms in the MHC genomic cluster are associated with several neuropsychiatric disorders, and in fact the MHC locus has the strongest association with schizophrenia. The Shatz lab further revealed that two classical MHCI genes (H-2Db and H-2Kb) are regulated by activity and required for the synaptic pruning that refines initial connections in the developing visual system. However, there are more than 50 MHCI genes, and yet to date, only these two have been studied in brain. I present here preliminary data that a non-classical MHCI, Qa-1, which has yet to be examined in the nervous system, is expressed by neurons in visual cortex. In the immune system, Qa-1 interacts with different receptors (CD94/NKG2s) than H-2Db and H-2Kb. I additionally present preliminary data that components of Qa- 1's cognate receptors, CD94/NKG2s, are also expressed by neurons. The central goal of this proposal is to use genetic, histological, electrophysiological, and biochemical techniques to elucidate functions of Qa-1 and its receptors in synaptic pruning and plasticity during development using the visual system as a model. I will specifically test the hypothesis that Qa-1 is a component of the pathway that executes activity-dependent changes in neural networks and that by interacting with different receptors than classical MHCIs, Qa-1 serves a distinct function in this developmental process. The long-term aim of this research is to contribute to our understanding of the molecular underpinnings for the pathophysiology of neurodevelopmental disorders.