Role of P2Y12 and Purinergic Signaling in Microglia-Mediated Synaptic Plasticity

P2Y12 和嘌呤能信号在小胶质细胞介导的突触可塑性中的作用

基本信息

批准号：
9015273
负责人：
Grayson Oren Sipe
金额：
$ 0.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9015273
关键词：
Acute Adult Affect Alzheimer&apos s Disease Animals Autistic Disorder Automobile Driving Behavior Biological Assay Biological Neural Networks Brain Cells Chemotactic Factors Chemotaxis Development Disease Electron Microscopy Epilepsy Feedback Genetic Genomics Health Image Immune Immune system Immunohistochemistry In Vitro Inflammation Inflammatory Knock-out Luciferases Measures Mediating Microglia Microscopy Modeling Morphology Mus Nerve Degeneration Nervous system structure Neurodevelopmental Disorder Neurons Neuropathy Ocular Dominance Optics Pathway interactions Peripheral Play Prevention strategy Process Purines Purinoceptor Rest Role Signal Transduction Synapses Synaptic plasticity Testing Therapeutic Visual system structure Wild Type Mouse area striata autocrine cell motility cell type chemokine clopidogrel critical period cytokine deprivation developmental plasticity experience imaging modality in vivo in vivo imaging luciferin macrophage monocular deprivation mouse model nervous system development nervous system disorder neurodevelopment neuroinflammation neuronal circuitry neurophysiology novel receptor coupling response tissue fixing two-photon vision development

项目摘要

DESCRIPTION (provided by applicant): Synaptic plasticity is critical for normal neurodevelopment and adult circuit function. Recent evidence suggests that microglia, classically studied in neuroinflammation, play critical roles in developmental synaptic plasticity. However, the mechanisms driving these roles are poorly understood. Purinergic signaling has been implicated in many neurodevelopmental processes, but studies on purinergic signaling in microglia have focused primarily on neuroinflammatory roles. It is unknown whether purinergic signaling contributes to the motility of non-inflamed microglia that underlies roles in synapse surveillance and plasticity. P2Y12 is a purinergic receptor associated with microglial motility and is highly expressed in resting, ramified microglia. However, P2Y12 is rapidly downregulated following inflammation, suggesting that it serves functions under healthy neurophysiological conditions. We propose that P2Y12 may be critical for basal microglial motility, synaptic surveillance, and synaptic plasticity. Using a mouse model, in Aim 1, we will determine whether genetic or pharmacological disruption of P2Y12 affects basal microglial morphology or motility in vivo. In Aim 2, we will test whether P2Y12 disruption affects microglial synaptic surveillance and experience-dependent synaptic plasticity in the mouse visual system. In addition, P2Y12 has been implicated in a purinergic autocrine system in peripheral macrophage chemotaxis, suggesting that a similar mechanism may exist in microglia. Therefore in Aim 3, we will test whether microglial release of purines in an autocrine manner is necessary for efficient chemotaxis towards chemokines implicated in synaptic plasticity. Through these studies, we will explore novel roles for purinergic signaling in non-inflamed microglia.

描述（由申请人提供）：突触可塑性对于正常神经发育和成人回路功能至关重要。最近的证据表明，经典的神经炎症研究小胶质细胞在发育突触可塑性中发挥着关键作用。然而，人们对驱动这些作用的机制知之甚少。嘌呤能信号传导与许多神经发育过程有关，但对小胶质细胞中嘌呤能信号传导的研究主要集中在神经炎症作用上。目前尚不清楚嘌呤能信号是否有助于非炎症小胶质细胞的运动，而非炎症小胶质细胞是突触监视和可塑性的基础。 P2Y12 是一种与小胶质细胞运动相关的嘌呤能受体在静止的分支小胶质细胞中高度表达。然而，P2Y12 在炎症后迅速下调，表明它在健康的神经生理条件下发挥作用。我们认为 P2Y12 可能对基础小胶质细胞运动、突触监视和突触可塑性至关重要。在目标 1 中，我们将使用小鼠模型确定 P2Y12 的遗传或药理学破坏是否会影响体内基底小胶质细胞的形态或运动性。在目标 2 中，我们将测试 P2Y12 破坏是否影响小鼠视觉系统中的小胶质细胞突触监视和经验依赖性突触可塑性。此外，P2Y12 与外周巨噬细胞趋化作用中的嘌呤能自分泌系统有关，表明小胶质细胞中可能存在类似的机制。因此，在目标 3 中，我们将测试小胶质细胞以自分泌方式释放嘌呤对于对与突触可塑性有关的趋化因子进行有效趋化是否是必要的。通过这些研究，我们将探索嘌呤能信号在非炎症小胶质细胞中的新作用。