Role of AMPA Receptor Reverse Signaling in Synapse Stability

描述（由申请人提供）：功能性神经元回路的建立依赖于过量突触的形成，随后是不适当连接的消除。虽然突触前输入的稳定对功能电路的发展和维持至关重要，但调节突触前稳定性的信号尚不清楚。我们的初步研究表明，皮层培养中的突触形成是高度动态的，并且在突触形成和消除的高速率背景下，涉及突触子集的稳定。在突触发生的高峰期，只有大约50%的假定突触在一小时内是稳定的。我们发现突触前的稳定性与突触后AMPA的存在密切相关，而与NMDA受体无关。我们已经确定LRRTM2是影响突触稳定性的glur2相互作用的跨膜蛋白。基于我们的初步研究，我们假设GluR2- LRRTM2复合物作为逆行信号调节突触前稳定性。本提案的具体目的是：目的1：确定GluR2受体的获得或丧失是否影响突触稳定性，并确定介导这种影响的GluR2结构域；目的2：确定GluR2和LRRTM2的相互作用的结构域，并确定LRRTM2被募集到突触位点的机制；为了确定GluR2-LRRTM2相互作用在调节突触前稳定性和突触功能中的作用，这些实验将为了解调节突触酶形成和稳定性的机制提供重要的见解。这些机制可能在神经系统疾病中被破坏，如Rett综合征、自闭症和阿尔茨海默病，这些疾病以突触丧失为特征，可能为治疗干预提供建议。公共卫生相关性：该项目的目标是了解在发育过程中调节大脑突触连接形成的分子机制。一些儿童神经系统疾病，如自闭症、Rett综合征和x连锁智力低下，都以突触连通性缺陷为特征。这个项目的发现应该指导人们更好地理解和开发这些疾病的治疗策略。

DESCRIPTION (provided by applicant): The establishment of functional neuronal circuits relies on the formation of excess synapses, followed by the elimination of inappropriate connections. Although the stabilization of presynaptic inputs is critical for the development and maintenance of functional circuits, the signals that regulate presynaptic stability are not known. Our preliminary studies suggest that synapse formation in cortical cultures is highly dynamic and involves the stabilization of a subset of synapses in a backdrop of a high rate of synapse formation and elimination. During the peak of synaptogenesis, only about 50% of putative synapses are stable over an hour. We have found that presynaptic stability is strongly correlated with the presence of postsynaptic AMPA but not NMDA receptors. We have identified LRRTM2 as a GluR2-interacting transmembrane protein that affects synapse stability. Based on our preliminary studies we hypothesize that a GluR2- LRRTM2 complex functions as a retrograde signal to regulate presynaptic stability. The specific aims of this proposal are: Aim 1: To determine whether gain or loss of GluR2 receptors affects synapse stability, and to identify the domains of GluR2 that mediate this effect Aim 2: To identify the domains of GluR2 and LRRTM2 that mediate their interaction and to identify the mechanism by which LRRTM2 is recruited to synaptic sites Aim 3: To determine the role of GluR2-LRRTM2 interactions in regulating presynaptic stability and synaptic function These experiments will provide important insights into the mechanisms that regulate synase formation and stability. These mechanisms are likely to be disrupted in neurological diisorders such as Rett Syndrome, Autism, and Alzheimer's disease that are characterized by loss of synapses and may suggest approaches for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand the molecular mechanisms that regulate the formation of synaptic connections in the brain during development. Several childhood neurological disorders, such as Autism, Rett Syndrome, and X-linked mental retardation are characterized by defects in synaptic connectivity. The findings of this project should guide efforts to better understand and develop therapeutic strategies for these disorders.