REGULATION OF GLUTAMATERGIC SYNAPSES BY LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN

描述（由申请人提供）：我们的长期目标是从分子水平上了解哺乳动物大脑中突触发育和功能的调节机制。大多数神经元能突触具有某些共同特征，例如突触后AMPA和NMDA受体的存在。同时，视突触前和突触后神经元的特性而定，突触能突触的结构和功能有很大的多样性。例如，海马体中的CA 3神经元从专门的棘上的齿状回（DG）轴突接收高度促进的苔藓纤维突触，称为多刺赘生物。相同的神经元在不高度促进的经典棘上接收联合/连合（A/C）神经元突触。CA 3 A/C突触与CA 3-CA 1 Schaffer侧支突触具有许多共同的结构特征和功能特性，表明它们可能由共同的分子机制指定。我们的初步研究表明，富含亮氨酸重复的跨膜蛋白LRRTM 2在调节海马神经元突触中起着关键作用。在这个提议中，我们希望确定LRRTM 2是否调节海马中特定类别的突触，以及它是否调节体内突触的结构和功能。公共卫生相关性：本项目的目标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。几种儿童神经系统疾病，如自闭症、雷特综合征和X连锁精神发育迟滞的特征在于突触连接和功能的缺陷。该项目的研究结果应指导更好地理解和制定这些疾病的治疗策略的努力。

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.