The correct development and connectivity of synapses is essential for the function of the central nervous system especially for synaptic plasticity, the brain capacity to adjust to changes through the development of post-natal synapses that ensure the long-term storage of sensory experiences. To guarantee that the inputs are translated into long-lasting changes in synapse structure and function, gene expression programs must be tightly regulated. The brain is characterized by abundant expression of several types of regulatory RNA species, such as lncRNAs, miRNAs and circular RNAs (circRNAs), which would regulate local and coordinated transcriptional and post-transcriptional regulation of gene expression. Cdr1as, is a mammalian-conserved, highly expressed, brain-enriched circRNA. It is predominantly expressed in excitatory neurons across cortex and moreover, strong evidence has shown a role of Cdr1as in normal brain function, arising as the most interesting candidate to study circRNA-exclusive action in brain. Cdr1as is regulated by a complex RNA network, that include several other non-coding RNAs. miR-7 is the main interactor in Cdr1as ncRNA network, is also evolutionarily conserved across vertebrates and considered to be a prototypical neuroendocrine miRNA. Nonetheless, the molecular interplay between Cdr1as and mir-7 in cortex neurons and their exact role in synaptic function is not yet understood. Here, we demonstrate that sustained neuronal depolarization induces the transcriptional up-regulation of Cdr1as and post-transcriptional stabilization of mature miR-7. We reveal a direct link between Cdr1as expression and regulation of glutamatergic transmission, which translated into dysfunctional bursting and network activity. We show how long-term overexpression of miR-7 is sufficient to rescue abnormal glutamate release and neuronal activity and decreases the number of Cdr1as molecules in neuronal projections. The lack of Cdr1as enhances direct and indirect global transcriptomic changes caused by miR-7 overexpression and specifically regulates secretion and synaptic plasticity pathways. Together, our results reveal that in cortical neurons miR-7 has a conserved role influencing secretion pathways, that is surveilled by Cdr1as, and the imbalance of Cdr1as-miR-7 buffer system directly affects glutamate transmission and neuronal connectivity, responsible for long-lasting alterations and plastic synaptic adaptations.
