REGULATION OF GLUTAMATERGIC SYNAPSES BY LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN

富含亮氨酸重复跨膜蛋白对谷氨酸突触的调节

• 批准号: 8013632
• 负责人: ANIRVAN GHOSH
• 金额: $ 31.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013632
• 关键词: AMPA Receptors; Affect; Autistic Disorder; Axon; Brain; Cell Surface Proteins; Cells; Childhood Neurological Disorder; Coculture Techniques; Defect; Dendritic Spines; Development; Disease; Excitatory Synapse; Frequencies; Glutamates; Goals; Health; Hippocampus (Brain); Integral Membrane Protein; Leucine-Rich Repeat; Molecular; Morphogenesis; Morphology; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Play; Population; Probability; Property; Regulation; Rett Syndrome; Role; Series; Specific qualifier value; Structure; Synapses; Tertiary Protein Structure; Therapeutic; Time; Vertebral column; X-Linked Mental Retardation; cell type; dentate gyrus; extracellular; hippocampal pyramidal neuron; in vivo; mossy fiber; postsynaptic; presynaptic; research study; small hairpin RNA; synaptogenesis

DESCRIPTION (provided by applicant): Our long-term goal is to gain a molecular understanding of the mechanisms that regulate the development and function of glutamatergic synapses in the mammalian brain. Most glutamatergic synapses share certain features, such as the presence of postsynaptic AMPA and NMDA receptors. At the same time, there is great diversity in the structure and function of glutamatergic synapses depending on the identity of the pre- and postsynaptic neuron. For example, CA3 neurons in the hippocampus receive highly facilitating mossy fiber synapses from Dentate Gyrus (DG) axons on specialized spines, called thorny excrescences. The same neurons receive association/commissural (A/C) neuron synapses on classical spines that are not highly facilitating. The CA3 A/C synapses share many structural features and functional properties with CA3-CA1 Schaffer collateral synapses, suggesting that they may be specified by common molecular mechanisms. Our preliminary studies suggest that the leucine rich repeat containing transmembrane protein LRRTM2 plays a critical role in regulating glutamatergic synapses in the hippocampus. In this proposal we wish to determine if LRRTM2 regulates specific classes of glutamatergic synapses in the hippocampus, and whether it regulates synapse structure and function in vivo. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand the role of a class of cell surface proteins in the establishment and function of excitatory synaptic connections. Several childhood neurological disorders, such as Autism, Rett Syndrome, and X-linked mental retardation are characterized by defects in synaptic connectivity and function. The findings of this project should guide efforts to better understand and develop therapeutic strategies for these disorders.

描述（由申请人提供）：我们的长期目标是对调节哺乳动物大脑中谷氨酸能突触的发育和功能的机制获得分子理解。大多数谷氨酸能突触具有某些特征，例如突触后AMPA和NMDA受体的存在。同时，根据前和突触后神经元的身份，谷氨酸能突触的结构和功能有很大的多样性。例如，海马中的CA3神经元从齿状回（DG）轴突（称为Thorny Excrescences）上获得高度促进的苔藓纤维突触。相同的神经元在不高度促进的经典棘突上接受了相关/合并（A/C）神经元的突触。 CA3 A/C突触具有许多结构特征和功能特性，其功能特性与CA3-CA1 Schaffer侧支突触，表明它们可以通过常见的分子机制指定。我们的初步研究表明，含有跨膜蛋白LRRTM2的富含亮氨酸的重复在调节海马中的谷氨酸能突触中起着至关重要的作用。在此提案中，我们希望确定LRRTM2是否调节海马中特定类别的谷氨酸能突触，以及它是否调节体内突触结构和功能。公共卫生相关性：该项目的目的是了解一类细胞表面蛋白在兴奋性突触连接的建立和功能中的作用。几种儿童时期神经系统疾病，例如自闭症，RETT综合征和X连锁的智力低下，其特征是突触连通性和功能的缺陷。该项目的发现应指导努力更好地理解和制定这些疾病的治疗策略。