Synapse Remodeling and Neuronal MHC Class I

突触重塑和神经元 MHC I 类

基本信息

批准号：
7246465
负责人：
Carla J Shatz
金额：
$ 8.54万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-02 至 2007-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7246465
关键词：
AMPA Receptors Action Potentials Address Adult Alzheimer&apos s Disease Antibodies Autistic Disorder Axon Binding Biochemical Brain Brain region CD3 Antigens Cell surface Childhood Chromosome Pairing Defect Development Disease regression Dyslexia Family Family member Genbank Gene Deletion Gene Family Genes Genetic Glutamate Receptor Goals Hippocampus (Brain)Histocompatibility Antigens Class I Human Immune system Immunohistochemistry Immunologic Receptors In Situ Hybridization In Vitro Individual Knockout Mice Learning Learning Disorders Life Light Logic Long-Term Depression Long-Term Potentiation MHC Class I Genes Mediating Memory Memory Disorders Messenger RNA Microelectrodes Molecular Mus Mutant Strains Mice Nerve Block Nervous system structure Neurons Neurophysiology - biologic function Pattern Peptides Phenotype Physiological Physiology Process Protein Overexpression Reading Research Research Proposals Retinal Ganglion Cells Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Slice Specificity Standards of Weights and Measures Structure Synapses Synaptic Potentials Synaptic Transmission Synaptic plasticity T-Cell Receptor TAP1 gene Transgenic Mice Transgenic Organisms Translating Translations Visual system structure Whole-Cell Recordings aging brain base beta-2 Microglobulin cell type critical developmental period design experience gain of function human leukocyte antigen gene langanite loss of function mRNA Expression member mutant neural circuit postsynaptic presynaptic protein distribution receptor relating to nervous system research study response trafficking uptake vision development

项目摘要

DESCRIPTION (provided by applicant): The long term goal of this research is to learn how experience during brain development, mediated by the activity-driven functioning of neural circuits, is translated into lasting structural change in synaptic connectivity. The specific goal of this research proposal is to examine the hypothesis that activity-dependent synaptic remodeling in development, and adult synaptic plasticity, involve a large gene family with well-known function in the immune system: MHC Class I genes (HLA genes in humans). Neuronal MHC Class I mRNA expression was discovered unexpectedly in an unbiased PCR-based differential screen for genes regulated by neural activity; initial genetic studies in mice lacking MHC I function then revealed a requirement for Class I MHC in visual system development and hippocampal plasticity (Huh et al, 2000). The goal of research proposed here is to learn more about how Class I MHC functions in the normal, uninjured CNS. Three specific aims are proposed. 1) Determine whether MHC Class I protein in neurons is located at synapses and whether there is a molecular logic to expression patterns of MHCI family members by means of immunohistochemistry, RT-PCR of specific brain regions, and in situ hybridization to examine CNS expression. 2) Determine how MHC Class I functions in bidirectional synaptic plasticity in the hippocampus by standard microelectrode recordings and biochemical assessment of glutamate receptor trafficking in hippocampal slices from wildtype, loss (B2m/TAP1) and gain of function (NSE-Db) mutant mice. 3) Determine if Class I MHC is necessary for the translation of neural activity into lasting anatomical change at synapses by examining structure and physiology of synapses in wild type and mutant hippocampal neurons in vitro following pharmacological manipulations that alter neural activity. The results of these experiments should broaden our understanding of how use-dependent changes, both in development and in adult, are encoded in the structure of neural circuits. Changes in synapses and circuits occur during critical periods of learning in childhood, as well as in memory formation throughout life. Understanding the molecules and mechanisms involved is also crucial for addressing and ultimately curing disorders of learning and memory, from Dyslexia, Autism and other learning disorders, to Alzheimer's and other memory disorders of the aging brain.

描述（由申请人提供）：这项研究的长期目标是了解大脑发育过程中的经验，由神经回路的活动驱动功能介导，如何转化为突触连接的持久结构变化。本研究计划的具体目标是检验以下假设：发育过程中活动依赖性突触重塑和成年突触可塑性涉及免疫系统中具有众所周知功能的大型基因家族：MHC I 类基因（人类 HLA 基因））。在基于 PCR 的无偏性筛选神经活动调节基因的差异筛选中，意外地发现了神经元 MHC I 类 mRNA 表达；对缺乏 MHC I 功能的小鼠进行的初步遗传学研究揭示了视觉系统发育和海马可塑性需要 I 类 MHC（Huh 等，2000）。这里提出的研究目标是更多地了解 I 类 MHC 在正常、未受伤的中枢神经系统中如何发挥作用。提出了三个具体目标。 1)通过免疫组化、特定脑区RT-PCR、原位杂交检测CNS表达等手段，确定神经元中MHC I类蛋白是否位于突触，以及MHCI家族成员的表达模式是否存在分子逻辑。 2) 通过标准微电极记录和对野生型、丧失 (B2m/TAP1) 和功能获得 (NSE-Db) 突变小鼠海马切片中谷氨酸受体运输的生化评估，确定 MHC I 类如何在海马双向突触可塑性中发挥作用。 3) 通过改变神经活动的药理操作，在体外检查野生型和突变型海马神经元突触的结构和生理学，确定 I 类 MHC 对于将神经活动转化为突触的持久解剖变化是否是必需的。这些实验的结果应该会拓宽我们对神经回路结构中如何编码发育和成人中使用依赖性变化的理解。突触和回路的变化发生在童年学习的关键时期，以及一生记忆形成的关键时期。了解所涉及的分子和机制对于解决和最终治愈学习和记忆障碍也至关重要，这些障碍包括阅读障碍、自闭症和其他学习障碍，到阿尔茨海默氏症和衰老大脑的其他记忆障碍。