Nogo receptor function at the synapse

描述（由申请人提供）：适当的神经系统功能关键取决于神经元回路的适当组装、维持和活性依赖性修饰。虽然很多是已知的细胞外分子和信号通路，调节轴突的生长和寻路在胚胎神经系统发育，相对较少的是知道的机制，控制突触的结构和功能，在幼年和成年哺乳动物的大脑和脊髓。越来越多的证据表明，在损伤的CNS中限制神经元发芽的分子参与者和在健康（未损伤）CNS中限制神经元可塑性的分子存在密切重叠。本实验室最近的研究表明，生长抑制蛋白Nogo/RTN 4和少突胶质细胞髓鞘糖蛋白（OMgp）以NgR 1依赖的方式抑制活动依赖性突触可塑性。NgR 1用于调节突触结构和突触传递的信号传导机制尚未确定。这项研究将采用小鼠遗传学、原代神经元细胞培养和基于生物化学的方法来确定Nogo/NgR 1下游调控的信号通路，主要关注PI 3 K/AKT/mTORC 1通路。在一个平行的方法中，电生理记录和药理学治疗的组合将被用来检查的分子机制，在先前的观察，NgR 1的损失衰减LTD在CA 3-CA 1突触，和Nogo 66的应用程序减少突触传递的LTP在CA 1神经元。NgR 1种系和条件突变体的行为研究将评估NgR 1信号在学习和记忆中的重要性。由于神经元结构和突触功能的变化通常与脑疾病相关，因此详细了解脑结构和功能如何调节在生物学和临床上都具有极大的意义。提出的实验是Nogo受体功能的系统分析，并有望提供神经系统生理学和病理学的关键方面的见解。

DESCRIPTION (provided by applicant): Proper nervous system function critically depends on the proper assembly, maintenance, and activity- dependent modification of neuronal circuits. Although a great deal is known about extracellular molecules and signaling pathways that regulate axonal growth and pathfinding during embryonic nervous system development, comparatively little is known about the mechanisms that control synaptic structure and function in the juvenile and adult mammalian brain and spinal cord. Mounting evidence suggests that there is a close overlap of molecular players that limit neuronal sprouting in the injured CNS, and molecules that restrict neuronal plasticity in the healthy (uninjured) CNS. Recent studies from our lab revealed that the growth inhibitory proteins Nogo/RTN4 and oligodendrocyte myelin glycoprotein (OMgp) suppress activity-dependent synaptic plasticity in an NgR1-dependent manner. The signaling mechanisms employed by NgR1 to regulate synaptic structure and synaptic transmission have not yet been defined. This research will pursue mouse genetic, primary neuronal cell culture, and biochemistry-based approaches to define the signaling pathways regulated downstream of Nogo/NgR1, with a primary focus on the PI3K/AKT/mTORC1 pathway. In a parallel approach, a combination of electrophysiological recordings and pharmacological treatments will be used to examine the molecular mechanisms underlying the previous observations that loss of NgR1 attenuates LTD at CA3-CA1 synapses, and that application of Nogo66 decreases LTP of synaptic transmission in CA1 neurons. Behavioral studies in NgR1 germline and conditional mutants will assess the importance of NgR1 signaling in learning and memory. Because changes in neuronal structure and synaptic function often correlate with brain disease, a detailed understanding of how brain structure and function is regulated is of great interest, both biologically and clinically. Experiments proposed are a systematic analysis of Nogo receptor function, and are expected to provide insights into key aspects of nervous system physiology and pathology.