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

• 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

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.

神经元采用一组嵌套的稳态机制来稳定网络活动变化时的放电率。突触缩减是稳态可塑性的一种形式，神经元响应网络活动的长期增加而削弱单一突触强度，特别是通过减少 AMPA 型谷氨酸受体 (AMPA-R) 的突触表达。稳态突触缩小对于活动依赖性神经元发育和神经系统疾病（例如癫痫）的病因学都很重要。然而，稳态突触缩小的分子基础在很大程度上尚不清楚。我们最近表明，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 是稳态突触缩小所必需的 (Fiore et al., 2014)。我们的定量蛋白质组学初步结果表明，大量突触基因的转录后下调（其中许多与突触后钙信号传导和 AMPA-R 磷酸化有关）是神经元对网络活动增加做出反应的标志。此外，我们获得了特定 miRNA 和 RBP 在突触基因转录后抑制协调中的作用的初步证据。在本提案中，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级的分子机制：1）表征新发现的基因在稳态下调过程中受到调节，重点关注候选基因 Atp2b4 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) 确定降尺度过程中突触基因转录后控制的协调机制，重点关注活性调节的 RNA 结合蛋白 Rbfox1 和 microRNA miR-129-5p 之间的串扰。 该项目的结果有望为响应神经网络慢性激活而执行和调节稳态可塑性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。

项目成果

A microRNA‐129‐5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses

microRNA-129-5p/Rbfox 串扰协调兴奋性突触的稳态下调

• DOI: 10.15252/embj.201695748
• 发表时间: 2017-06-14
• 期刊: The EMBO Journal
• 作者: M. Rajman;F. Metge;R. Fiore;S. Khudayberdiev;A. Aksoy;S. Bicker;Cristina Ruedell Reschke;Rana Raoof;G. Brennan;N. Delanty;Michael A. Farrell;Donncha F. O’Brien;S. Bauer;B. Norwood;M. Venø;M. Krüger;T. Braun;J. Kjems;F. Rosenow;D. Henshall;C. Dieterich;G. Schratt
• 通讯作者: G. Schratt

Personalized translational epilepsy research — Novel approaches and future perspectives Part I: Clinical and network analysis approaches

个性化转化癫痫研究 â 新方法和未来前景第 I 部分：临床和网络分析方法

• DOI: 10.1016/j.yebeh.2017.06.041
• 发表时间: 2017
• 期刊: Epilepsy & Behavior
• 影响因子: 2.6
• 作者: Rosenow F; van Alphen N; Becker A; Chiocchetti A; Deichmann R; Deller T; Freiman T; Freitag CM; Gehrig J; Hermsen AM; Jedlicka P; Kell C; Klein KM; Knake S; Kullmann DM; Liebner S; Norwood BA; Omigie D; Plate K; Reif A; Reif PS; Reiss Y; Roeper J; Ronelle
• 通讯作者: Ronelle

Personalized translational epilepsy research — Novel approaches and future perspectives Part II: Experimental and translational approaches

个性化转化癫痫研究 â 新方法和未来前景第二部分：实验和转化方法

• DOI: 10.1016/j.yebeh.2017.06.040
• 发表时间: 2017
• 期刊: Epilepsy & Behavior
• 影响因子: 2.6
• 作者: Bauer S; van Alphen N; Becker A; Chiocchetti A; Deichmann R; Deller T; Freiman T; Freitag CM; Gehrig J; Hermsen AM; Jedlicka P; Kell C; Klein KM; Knake S; Kullmann DM; Liebner S; Norwood BA; Omigie D; Plate K; Reif A; Reif PS; Reiss Y; Roeper J; Ronellenf
• 通讯作者: Ronellenf

Electrical stimulation of the ventral hippocampal commissure delays experimental epilepsy and is associated with altered microRNA expression

电刺激腹侧海马连合可延迟实验性癫痫，并与 microRNA 表达改变相关

• DOI: 10.1016/j.brs.2019.06.009
• 发表时间: 2019-11-01
• 期刊: Brain Stimulation
• 影响因子: 7.7
• 作者: L. Costard;V. Neubert;M. Venø;Junyi Su;J. Kjems;N. Connolly;J. Prehn;G. Schratt;D. Henshall;F. Rosenow;S. Bauer
• 通讯作者: S. Bauer