microRNA-218-5p coordinates scaling of excitatory and inhibitory synapses during homeostatic synaptic plasticity

• 成果类型: Article
• 署名作者: Colameo, David; Maley, Sara M.; Winterer, Jochen; ElGrawani, Waleed; Gilardi, Carlotta; Galkin, Simon; Fiore, Roberto; Brown, Steven A.; Schratt, Gerhard
• 署名单位: Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12720
• DOI: 10.1073/pnas.2500880122
• 发表日期: 2025-04-08
• 关键词: sleep-deprivation; expression; epilepsy; homer1a; package; balance; memory

摘要

Homeostatic synaptic plasticity (HSP) is a neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating these processes are unknown. In this study, we investigate the role of miR- 218- 5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)- induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of microRNA- binding sites in genes changing upon PTX- induced HSD, we bioinformatically predict and experimentally validate increased miR- 218- 5p activity upon PTX treatment. By electrophysiological recordings and confocal microscopy, we demonstrate that inhibiting miR- 218- 5p activity exerts a dual effect during HSD: It occludes the downscaling of excitatory synapses and dendritic spines, while at the same time attenuating inhibitory as a direct miR- 218- 5p target which potentially mediates the effect of miR- 218- 5p on homeostatic upscaling of inhibitory synapses. By performing long- term electroencephalographic recordings, we further reveal that local inhibition of miR- 218- 5p in the somasummary, this study uncovers miR- 218- 5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity- induced perturbations, with implications for pathophysiology.