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

 描述(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，以及调节内环境平衡。在发育过程中，神经元必须连接到精确的神经网络中，才能驱动这些复杂的行为。最初，神经元进行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对这些连接进行细化。活动依赖机制是发育中的大脑成熟所必需的，最近被认为是包括精神分裂症和自闭症谱系障碍在内的几种神经精神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，通过分子程序的活动来精炼发育中的神经回路。沙茨实验室的研究发现，主要组织相容性复合体I类(MHCI)蛋白在依赖活动的神经网络改进中扮演着令人惊讶的角色。在神经元中观察到MHCI的表达是意想不到的，因为大脑历来被认为是一个免疫保护的环境，MHCI分子的成熟功能是在免疫系统中，在那里它们参与识别自我和异物。此外，MHC基因在神经元中的存在也是值得注意的，因为在全基因组关联研究中，MHC基因组簇的多态与几种神经精神疾病有关，事实上MHC基因与精神分裂症的相关性最强。沙茨实验室进一步揭示，两个经典的MHCI基因(H-2db和H-2kb)受活动调节，并需要进行突触修剪，以完善发育中的视觉系统中的初始连接。然而，有50多个MHCI基因，到目前为止，只有这两个基因在大脑中进行了研究。我在这里提供的初步数据表明，一种非经典的MHCI，Qa-1，还没有在神经系统中被检测到，它是由视觉皮质中的神经元表达的。在免疫系统中，Qa-1与不同的受体(CD94/NKG2s)相互作用，而不是H-2db和H-2kb。此外，我还提供了初步数据，即QA-1‘S同源受体CD94/NKG2的成分也在神经元中表达。这项建议的中心目标是利用遗传学、组织学、电生理学和生化技术，以视觉系统为模型，阐明QA-1及其受体在突触修剪和发育过程中的可塑性中的功能。我将专门测试这一假设，即Qa-1是在神经网络中执行活动依赖变化的通路的一个组成部分，并且通过与不同于经典MHCI的受体相互作用，Qa-1在这一发育过程中发挥着不同的功能。这项研究的长期目标是帮助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.