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

Abstract

The 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 cortical murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induces two-fold transcriptional upregulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss causes doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, the periodicity of neuronal networks increases, and synchronicity is impaired. Strikingly, these effects are reverted by sustained expression of miR-7, which also clears Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression are stronger (including miR-7-targets downregulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in cortical neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.

Synopsis

In mouse cortical neurons, miR-7 regulates glutamate release, controlled by the buffering action of Cdr1as. These molecules together govern glutamatergic transmission and neuronal connectivity, influencing synaptic adaptations at transcriptional and neuronal activity levels.

• Neuronal depolarization transcriptionally induces Cdr1as and post-transcriptionally stabilizes miR-7

• Cdr1as-KO neurons show chronically elevated neuronal activity, higher asynchrony and oscillation, increased pre-synaptic glutamate release, and inhibition of synaptic adaptation.

• Cdr1as:miR-7 interaction exerts a synergetic gene regulation of the neuronal transcriptome, compared to their individual mutations. Additionally, miR-7 up-regulation is sufficient to restore local and network neural activity and glutamate secretion, but it depends on Cdr1as expression.

Abstract

In mouse cortical neurons, miR-7 regulates glutamate release, controlled by the buffering action of Cdr1as. These molecules together govern glutamatergic transmission and neuronal connectivity, influencing synaptic adaptations at transcriptional and neuronal activity levels.