A tripartite circRNA/mRNA/miRNA interaction regulates glutamatergic signaling in the mouse brain

Functional studies of circular RNAs (circRNAs) began quite recently, and few data exist on their function in vivo. Here, we have generated a knockout (KO) mouse model to study circDlc1(2), a circRNA highly expressed in the prefrontal cortex and striatum. The loss of circDlc1(2) led to the upregulation of glutamatergic-response-associated genes in the striatal tissue, enhanced excitatory synaptic transmission in neuronal cultures, and hyperactivity and increased stereotypies in mice. Mechanistically, we found that circDlc1(2) physically interacts with some mRNAs, associated with glutamate receptor signaling (gluRNAs), and with miR-130b-5p, a translational regulator of these transcripts. Notably, differently from canonical microRNA (miRNA) “sponges,” circDlc1(2) synergizes with miR-130b-5p to repress gluRNA expression. We found that circDlc1(2) is required to spatially control miR-130b-5p localization at synaptic regions where gluRNA is localized, indicating a different layer of regulation where circRNAs ensure robust control of gene expression via the correct subcellular compartmentalization of functionally linked interacting partners. [Display omitted] •KO mouse model reveals circDlc1(2) role in glutamatergic gene regulation and behavior•Loss of circDlc1(2) enhances synaptic transmission, leading to hyperactivity in mice•circDlc1(2) and miR-130b-5p interact and control gluRNA expression synergistically•circDlc1(2) controls miR-130b-5p synaptic localization Silenzi et al. report that the loss of circDlc1(2) in a KO mouse model upregulates glutamatergic genes, enhances synaptic transmission, and causes hyperactivity. circDlc1(2) interacts with gluRNA and miR-130b-5p, synergizing with the latter to repress gluRNA expression. It also spatially controls miR-130b-5p localization, highlighting an unprecedented gene regulation mechanism.