miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner

Abstract

AbstractThe circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary forebrain murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induced two-fold transcriptional up-regulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss caused doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, periodicity of neuronal networks was increased and synchronicity was impaired. Strikingly, these effects were reverted by sustained expression of miR-7 which also cleared Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression were stronger (including miR-7-targets down-regulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in forebrain neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.