Nogo receptor function at the synapse

描述(由申请人提供)：正确的神经系统功能关键取决于神经回路的适当组装、维护和活动依赖的修饰。虽然在胚胎神经系统发育过程中调节轴突生长和寻路的细胞外分子和信号通路已经知道很多，但对幼年和成年哺乳动物脑和脊髓中控制突触结构和功能的机制知之甚少。越来越多的证据表明，在受损的中枢神经系统中，限制神经元萌发的分子与在健康的(未受伤的)中枢神经系统中限制神经元可塑性的分子密切重叠。我们实验室最近的研究表明，生长抑制蛋白Nogo/RTN4和少突胶质细胞髓磷脂糖蛋白(OMgp)以NgR1依赖的方式抑制活性依赖的突触可塑性。NgR1调节突触结构和突触传递的信号机制尚未明确。这项研究将采用小鼠遗传学、原代神经细胞培养和基于生物化学的方法来确定Nogo/NgR1下游调控的信号通路，主要集中在PI3K/AKT/mTORC1通路上。在一种平行的方法中，电生理记录和药物治疗的结合将被用来检验先前观察到的NgR1的丢失减弱CA3-CA1突触的LTD的分子机制，以及应用Nogo66降低CA1神经元突触传递的LTP。对NgR1胚系和条件突变体的行为研究将评估NgR1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往往与脑疾病相关，因此详细了解大脑结构和功能是如何调节的，无论在生物学上还是临床上都是非常有意义的。提出的实验是对Nogo受体功能的系统分析，有望为神经系统生理学和病理学的关键方面提供见解。

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.