Cortical miR-709 links glutamatergic signaling to NREM sleep EEG slow waves in an activity-dependent manner

• 成果类型: Article
• 署名作者: Kompotis, Konstantinos; Mang, Geraldine M.; Hubbard, Jeffrey; Jimenez, Sonia; Emmenegger, Yann; Polysopoulos, Christos; Hor, Charlotte N.; Wigger, Leonore; Hebert, Sebastien S.; Mongrain, Valerie; Franken, Paul
• 署名单位: University of Lausanne; University of Zurich; Swiss School of Public Health (SSPH+); University of Zurich; University of Lausanne; Laval University; Laval University Hospital; Laval University; Universite de Montreal; Universite de Montreal; Universite de Montreal
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10961
• DOI: 10.1073/pnas.2220532121
• 发表日期: 2024-01-16
• 关键词: nmda receptors; neurons; dicer; morphogenesis; stimulation; TRAFFICKING; oscillation; homeostasis; expression; plasticity

摘要

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD) altered; while the rapid-eye-movement sleep (REMS) rebound was compromised in both, the increase in EEG delta (1 to 4 Hz) power during non-REMS (NREMS) was smaller in cKO mice and larger in icKO mice compared to controls. We subsequently investigated the effects of SD on the forebrain miRNA transcriptome and found that the expression of 48 miRNAs was affected, and in particular that of the activity-dependent miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75 to 1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates genes involved in glutamatergic neurotransmission. A subset of these genes was also affected in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal activity during wakefulness to brain synchrony during sleep through the regulation of glutamatergic signaling.