Synaptic Refinement in the Thalamus

丘脑突触细化

• 批准号: 8269090
• 负责人: Zhong-Wei Zhang
• 金额: $ 37.3万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269090
• 关键词: Acute; Adult; Animals; Anxiety Disorders; Autistic Disorder; Behavior; Brain; Brain Diseases; Cells; Complex; Development; Disease; Electron Microscopy; Environment; Epilepsy; Genes; Genetic; Goals; Health; Heterogeneity; Learning; Life; Mediating; Memory; Modeling; Molecular; Mood Disorders; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuronal Injury; Neuronal Plasticity; Neurons; Newborn Infant; Pathway interactions; Pharmacology; Play; Preparation; Process; Property; Public Health; Regulation; Research; Role; Schizophrenia; Sensory; Sensory Deprivation; Slice; Synapses; System; Thalamic structure; Vibrissae; base; critical period; deprivation; early experience; experience; genetic analysis; improved; information processing; insight; light microscopy; mature animal; nerve injury; nervous system development; neural circuit; novel; patch clamp; response; somatosensory; transmission process

DESCRIPTION (provided by applicant): The refinement of neuronal connections, which consists of selective elimination and consolidation of synapses, is a key mechanism of neuroplasticity. Disruptions of this process, caused by either environmental or genetic factors or both, are thought to be a substrate for altered information processing and abnormal behaviors associated with common developmental brain disorders including autism and schizophrenia. Mechanisms underlying synaptic refinement during development may also be involved in plasticity in the adult brain associated with learning, memory, and neuronal injuries. The long-term goal of this research is to understand how neurons in immature brains selectively eliminate some synapses while reinforcing others. We use sensory relay synapses in the thalamus of the mouse as a model to investigate the cellular and molecular mechanisms underlying synaptic refinement. We will use a novel slice preparation to quantitatively analyze the number and properties of synapses at the single-cell level in whisker sensory relay neurons in the thalamus of normal and genetically modified mice. We will determine the structural basis of synaptic refinement through quantitative analyses of the synapse using light and electron microscopy. Specific Aim 1 proposes to analyze the effects of sensory deprivation and identify the underlying cellular and molecular mechanisms. We hypothesize that sensory experience plays a critical role in developmental refinement of the synapse. Specific Aim 2 proposes to investigate the roles of NMDA (N-methyl-D-aspartate) receptor subunits NR2A and NR2C at this synapse. We hypothesize that the developmental switch of NMDA receptor composition plays an important role in synaptic refinement. PUBLIC HEALTH RELEVANCE This research will advance our understanding of autism, epilepsy, mood and anxiety disorders, and schizophrenia, and may provide opportunity for the development of new and improved treatments for neural injury.

描述（由申请人提供）：神经元连接的完善，由选择性消除和巩固突触组成，是神经可塑性的关键机制。由于环境或遗传因素或两者兼而有之，该过程的破坏被认为是信息处理的改变和与常见发育性脑部疾病有关的改变，包括自闭症和精神分裂症。发育过程中突触改进的基础机制也可能参与与学习，记忆和神经元损伤相关的成人大脑的可塑性。这项研究的长期目标是了解未成熟大脑中的神经元如何有选择地消除某些突触，同时加强其他突触。我们在小鼠的丘脑中使用感觉继电器突触作为模型，以研究突触改进的细胞和分子机制。我们将使用一种新型的切片制剂来定量分析正常和转基因小鼠的丘脑中晶须感觉中继神经元中突触的数量和特性。我们将通过使用光和电子显微镜对突触进行定量分析来确定突触改进的结构基础。特定目的1提出了分析感觉剥夺的影响并确定潜在的细胞和分子机制。我们假设感觉体验在突触的发展改进中起着至关重要的作用。具体目的2提议研究此突触对NMDA（N-甲基-D-天冬氨酸）受体亚基NR2A和NR2C的作用。我们假设NMDA受体组成的发育转换在突触改进中起重要作用。公共卫生相关性这项研究将提高我们对自闭症，癫痫，情绪和焦虑症和精神分裂症的理解，并可能为开发新的和改善神经损伤的治疗方法提供机会。