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Identification of novel functional and post-transcriptional regulatory mechanisms during homeostatic synaptic downscaling

稳态突触降尺度过程中新型功能和转录后调节机制的鉴定

基本信息

批准号：
322038698
负责人：
Dr. Roberto Fiore, Ph.D.
金额：
--
依托单位：
Institut für Neurowissenschaften
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/322038698?language=en
关键词：
Identification novel functional post transcriptional

项目摘要

Neurons employ a nested set of homeostatic mechanisms to stabilize firing rates in the face of changes in network activity. Synaptic downscaling is one form of homeostatic plasticity where neurons weaken unitary synaptic strength in response to a chronic increase in network activity, in particular by decreasing synaptic expression of AMPA-type glutamate receptors (AMPA-R). Homeostatic synaptic downscaling is important both in activity-dependent neuronal development and in the etiology of neurological disorders, such as epilepsy. However, the molecular underpinnings of homeostatic synaptic downscaling are largely unknown. We have recently shown that the neuronal microRNA miR-134 is required for homeostatic synaptic downscaling in a rat hippocampal culture model by post-transcriptional control of the RNA-binding protein (RBP) Pumilio-2 (Fiore et al., 2014). Our preliminary results from quantitative proteomics suggest that the post-transcriptional downregulation of a plethora of synaptic genes, many of which are linked to postsynaptic calcium signaling and AMPA-R phosphorylation, is a hallmark of the neuronal response to increased network activity. Furthermore, we obtained preliminary evidence for a role of specific miRNAs and RBPs in the coordination of post-transcriptional inhibition of synaptic genes.In this proposal we plan to further elucidate the molecular mechanisms that regulate and execute homeostatic synaptic downscaling by1) Characterizing the function of newly identified genes regulated during homeostatic downscaling, focusing on the candidates Atp2b4 and Dcx and their interaction at the level of calcium signaling and AMPA-R trafficking and function. 2) Identifying the coordinated mechanisms underlying the post-transcriptional control of synaptic genes during downscaling, focusing on a crosstalk between the activity-regulated RNA-binding protein Rbfox1 and the microRNA miR-129-5p. The results from this project promise to provide significant new insight into the molecular mechanisms that execute and regulate homeostatic plasticity in response to chronic activation of neural networks, with important implications for activity-dependent neuronal development and neurological disorders characterized by impaired homeostatic plasticity, including epilepsy.

神经元采用一套嵌套的稳态机制来稳定网络活动变化时的放电率。突触降尺度是稳态可塑性的一种形式，其中神经元响应于网络活动的慢性增加而减弱单一突触强度，特别是通过减少AMPA型谷氨酸受体（AMPA-R）的突触表达。稳态突触降尺度在活动依赖性神经元发育和神经系统疾病（如癫痫）的病因学中都很重要。然而，稳态突触降尺度的分子基础在很大程度上是未知的。我们最近已经表明，在大鼠海马培养模型中，通过RNA结合蛋白（RBP）Pumilio-2的转录后控制，神经元microRNA miR-134是稳态突触缩小所需的（Fiore et al.，2014年）。定量蛋白质组学的初步结果表明，转录后下调的突触基因，其中许多是与突触后钙信号和AMPA-R磷酸化，是一个标志的神经元反应增加网络活动。此外，我们还获得了特定的miRNA和RBP在协调突触基因转录后抑制中的作用的初步证据。在本研究中，我们计划通过以下方式进一步阐明调节和执行稳态突触降尺度的分子机制：1）表征稳态降尺度过程中新鉴定的受调节基因的功能，重点关注候选物Atp 2b 4和Dcx及其在钙信号传导和AMPA-R运输和功能水平上的相互作用。2)确定在缩小过程中突触基因转录后控制的协调机制，重点是活性调节RNA结合蛋白Rbfox 1和microRNA miR-129- 5 p之间的串扰。该项目的结果有望为执行和调节稳态可塑性以响应神经网络的慢性激活的分子机制提供重要的新见解，对活动依赖性神经元发育和以稳态可塑性受损为特征的神经系统疾病（包括癫痫）具有重要意义。