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

Abstract

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 rapid-eye-movement sleep (REMS) rebound was compromised in both, EEG delta (1-4 Hz) power during non-REM sleep (NREMS) was reduced in cKO mice and increased in icKO mice. We subsequently investigated the effects of SD on the miRNA transcriptome and found that the expression of 48 forebrain miRNAs was affected, in particular, the activity-dependent miRNA miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75-1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates endosomal trafficking and glutamatergic receptor activity. A subset of the genes involved in glutamatergic transmission was affected also 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 excitability during wakefulness to brain synchrony during sleep, likely through the regulation of endosomal trafficking and glutamatergic signaling.

Non-coding RNAs and neuroinflammation: implications for neurological disorders

“…Interestingly, both miR-15/ 16 and miR-709 have important roles in controlling neuroinflammation in vivo. miR-709 controls glutamatergic signaling and endosomal trafficking in cortical neurons, resulting in balanced sleep-wake cycles [135]. The deletion of mir-15/16 in T-regulatory cells results in animals with extensive lymphoproliferative disease and systemic tissue inflammation [136].…”