Exploring RGS14 signaling functions in the CA2 hippocampus

描述(申请人提供)：我们最近发现RGS14是一种新的抑制CA2海马神经元突触可塑性/LTP和基于海马区的学习和记忆的基因。这些研究首次将这个基因/蛋白(RGS14)和这个海马区(CA2)与与学习和记忆有关的突触可塑性联系起来。关于大脑中神秘的CA2区，那里的驻留基因，或者RGS14调节LTP的潜在分子机制(S)，人们知之甚少。我们发现RGS14是一种多功能的支架蛋白，它整合了G蛋白和H-Ras/Raf/ERK信号来抑制某些形式的生长因子介导的MAP激酶信号。RGS14包含结合活性Gi/o1-GTP(RGS结构域)、非活性Gi11/2-GDP(GPR/GL结构域)以及活性H-RAS/Rap2和Raf(串联RAS结合域，或RBD)的特定结构域。在CA2神经元中已经发现了其他几种信号蛋白和信号通路，它们调节LTP，也与RGS14结合伙伴(Gi/o-连接的A1腺苷受体，与H-Ras/Raf/MAP激酶信号连接的EGF和FGFTyr-Kinase受体)相连。我的工作假设是，RGS14整合了关键的信号通路，这些信号通路对于调节海马CA2区神经元的突触可塑性至关重要。这些研究的目标将是开发实验工具，并确定(为未来研究)RGS14与CA2神经元连接以调节突触可塑性的分子信号通路。具体目标是：目标1：开发新的慢病毒传递系统，使我们能够挽救CA2神经元失去的RGS14功能(抑制LTP)，并测试RGS14在CA1神经元的表达是否抑制那里的突触可塑性。目的：建立编码RGS14靶向功能缺失突变的新型慢病毒，以确定不同的RGS14信号伙伴/通路在CA2突触可塑性/LTP调节中的作用。目的3：确定RGS14如何与调节CA2神经元LTP的已知信号机制相互作用。影响：这些研究将产生新的实验工具，将确定RGS14的哪些已确定的信号功能对其在CA2神经元中的作用最重要(从而有助于指导未来的研究)，并建立RGS14与CA2神经元中哪些已知途径相互作用，调节突触可塑性，对关键的人类认知功能至关重要。 与公共健康相关：这些研究将定义新的分子机制，这些机制构成正常生理过程的基础，如学习和记忆，以及在人类疾病状态下改变的社会行为，如精神分裂症或自闭症和双相情感障碍。

DESCRIPTION (provided by applicant): We recently discovered that RGS14 is a novel suppressor of both synaptic plasticity/LTP in CA2 hippocampal neurons and hippocampal-based learning and memory. These studies are the first to implicate this gene/protein (RGS14) and this hippocampal region (CA2) in synaptic plasticity relating to learning and memory. Very little is known about the enigmatic CA2 region of brain, the resident genes there, or the underlying molecular mechanism(s) by which RGS14 regulates LTP there. We have found that RGS14 is a multifunctional scaffolding protein that integrates G protein and H-Ras/Raf/ERK signaling to inhibit certain forms of growth factor-directed MAP kinase signaling. RGS14 contains specific domains that bind active Gi/o1-GTP (RGS domain), inactive Gi11/2-GDP (GPR/GL domain) and active H-Ras/Rap2 and Raf (tandem Ras binding domains, or RBD). Several other signaling proteins and pathways have been identified in CA2 neurons that modulate LTP there, and that also link to RGS14 binding partners (Gi/o-linked A1 adenosine receptors, EGF and FGF Tyr-kinase receptors linked to H-Ras/Raf/MAP kinase signaling). My working hypothesis is that RGS14 integrates key signaling pathways that are critical for regulating synaptic plasticity in hippocampal CA2 neurons. The goal for these studies will be to develop experimental tools and to identify (for future study) molecular signaling pathways that RGS14 interfaces with in CA2 neurons to modulate synaptic plasticity. The Specific Aims will be to: Aim 1: Develop novel lentiviral delivery systems that will allow us to rescue lost RGS14 function (inhibition of LTP) in CA2 neurons, and to test if expression of RGS14 in CA1 neurons suppresses synaptic plasticity there. Aim 2: Develop novel lentiviruses encoding targeted loss-of-function mutations of RGS14 that will determine the role of the different RGS14 signaling partners/pathways in the regulation of CA2 synaptic plasticity/LTP. Aim 3: Determine how RGS14 interacts with known signaling mechanisms that regulate LTP in CA2 neurons. IMPACT: These studies will generate new experimental tools that will determine which of the identified signal functions of RGS14 are most important for its actions in CA2 neurons, (thereby helping to direct future studies), and establish what known pathways in CA2 neurons RGS14 interacts with to regulate synaptic plasticity important for key human cognitive functions. PUBLIC HEALTH RELEVANCE: These studies will define novel molecular mechanisms that underlie normal physiological processes such as learning and memory and social behaviors that are altered in human disease states such as schizophrenia or the autism and bipolar spectrum of disorders.