REGULATION OF GLUTAMATERGIC SYNAPSES BY LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN

描述(申请人提供)：我们的长期目标是对哺乳动物大脑中谷氨酸能突触发育和功能的调控机制有一个分子上的了解。大多数谷氨酸能突触都有某些特征，如突触后AMPA和NMDA受体的存在。同时，谷氨酸能突触的结构和功能因突触前和突触后神经元的不同而有很大的差异。例如，海马区的CA3神经元从特殊脊椎上的齿状回(DG)轴突接收高度便利的苔藓纤维突触，称为棘突。同样的神经元接受经典脊椎上的联合/连合(A/C)神经元突触，这并不是高度便利的。CA3A/C突触与CA3-CA1侧支突触具有许多共同的结构特征和功能特性，提示它们可能是由共同的分子机制决定的。我们的初步研究表明，富含亮氨酸重复序列的跨膜蛋白LRRTM2在调节海马区谷氨酸能突触中起着关键作用。在这项建议中，我们希望确定LRRTM2是否调节海马体中特定类别的谷氨酸能突触，以及它是否调节体内突触的结构和功能。公共卫生相关性：该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。一些儿童神经疾病，如自闭症、Rett综合征和X-连锁智力低下，其特征是突触连接和功能缺陷。该项目的研究结果将指导人们更好地理解和制定针对这些疾病的治疗策略。

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.