mGluR5 hypoactivity is integral to glutamatergic dysregulation in schizophrenia

项目摘要 (意义)多条证据表明mGluR5信号与病理生理和 精神分裂症的治疗；但mGluR5信号可能的失调及其病理生理作用 目前还不得而知。最近，我们发现了尸检中mGluR5信号减少的直接证据 精神分裂症患者的背外侧前额叶皮质。MGluR5与 突触后密度(PSD)中的NMDA受体(GLUN)复合体和这两条途径促进 彼此的活动。(初步研究)我们检测了激动剂诱导的mGluR5信号的激活 在死后17对配对患者的背外侧前额叶皮质(DLPFC)中 控制。我们发现mGluR5受体激活下游的三条途径显著减少；即， 与对照组相比，GQ/11激活和招募PI3K和支架蛋白(P&lt；0.01)。这 伴随着mGluR5磷酸化的失调，mGluR5对受体来说是重要的 脱敏，并在mGluR5与RGS4，Presso 1，Norbin和Tamalin，这是关键的 表面表达和聚集性。重要的是，我们发现了支持破坏互惠促进的证据 在精神分裂症的mGluR5和Glun信号之间，因此一个人的功能减退可以进一步损害 另一个。(科学假设)精神分裂症与mGluR5信号传导途径低活性有关 改变受体复合体中mGluR5的磷酸化和蛋白质-蛋白质相互作用(PrPrIs)。MGluR5 功能减退可导致GLUN信号失活，反之亦然。 促进。相互作用体中的PrRIs可能是病因的汇合点。(具体目标) 进一步研究精神分裂症中mGluR5活性低下及其与Glun信号的相互作用，我们将 在DLPFC中检测mGluR5在Glun信号上活性低下的分子基础，反之亦然 将患者与对照组进行比较。(目标1)。我们的初步数据和最近的研究表明，PrIs是底物 在此基础上，各种分子变化汇聚在一起，导致谷氨酸能失调。组合 发现和定量蛋白质组学，我们将分析mGluR5-Glun相互作用组中PrI的变化 患者的基础水平和对受体激活的反应(目标2)。相互作用体中的PrPrI改变 可以在基因组、转录和蛋白质组水平上追溯到它们的病因学基础。切割 EDGE系统生物学算法允许我们利用目前可用的最大基因组数据集 计算相同数量受试者的DLPFC转录组数据。基因变异，归因于转录型 结果，连同定量的PSD蛋白质组学结果将使用热投射到交互组上 基于扩散的算法(目标3)。这将确定病因上的重大意义和潜在的目标 互动体中的子网络。(IMPACT)我们将建立mGluR5功能低下作为谷氨酸能不可分割的部分 精神分裂症的调节失调，并确定病因基础和潜在的干预点。

Project Summary (Significance) Multiple lines of evidence have implicated mGluR5 signaling for the pathophysiology and treatment of schizophrenia; yet possible dysregulation of mGluR5 signaling and their pathophysiologic roles are presently unknown. Recently, we found direct evidence for reduced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. mGluR5 is physically connected with NMDA receptor (GluN) complexes in the postsynaptic density (PSD) and these two pathways facilitate the activity of each other. (Preliminary Studies) We examined the agonist-induced activation of mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 matched pairs of patients and controls. We found a striking reduction in three pathways downstream to mGluR5 receptor activation; namely, Gq/11 activation and recruitment of PI3K and scaffolding proteins compared to controls (P<0.01). This dysregulation was accompanied by alterations in phosphorylation of mGluR5, important for receptor desensitization, and in mGluR5 association with RGS4, Preso 1, norbin and tamalin, which are critical for surface expression and clustering. Importantly, we find evidence supporting disruption of reciprocal facilitation between mGluR5 and GluN signaling in schizophrenia and thus hypofunction of one can further compromise the other. (Scientific Premise) Schizophrenia is associated with mGluR5 signaling hypoactivity mediated by altered mGluR5 phosphorylation and protein – protein interactions (PrPrIs) in the receptor complexes. mGluR5 hypofunction can contribute to GluN signaling hypoactivity and vice versa via disruption of reciprocal facilitation. PrPrIs in the interactome may be a point of convergence for etiologic factors. (Specific Aims) To further characterize mGluR5 hypoactivity and its interplay with GluN signaling in schizophrenia, we will examine molecular underpinnings for mGluR5 hypoactivity on GluN signaling and vice versa in the DLPFC of patients compared to controls. (Aim 1). Our preliminary data and recent studies point to PrPrIs as substrates upon which various molecular alterations converge and precipitate glutamatergic dysregulation. Combining discovery and quantitative proteomics, we will analyze PrPrI alterations in the mGluR5-GluN interactome in patients at the basal level and in response to receptor activation (Aim 2). PrPrI alterations in the interactome can be traced to their etiologic underpinnings at the genomic, transcriptomic and proteomic levels. Cutting edge systems biology algorithms permit us to leverage largest genomics data sets presently available and impute DLPFC transcriptomics data of the same number of subjects. Genetic variants, imputed transcriptomic results, along with quantitative PSD proteomics results will be projected onto the interactome using heat diffusion based algorithms (Aim 3). This will identify etiologically significant and potentially targetable subnetworks in the interactome. (Impact) We will establish mGluR5 hypofunction as integral to glutamatergic dysregulation in schizophrenia and identify etiologic underpinnings and potential points of intervention.