Much remains too be learned about the function of circular RNAs, which are particulary enriched in neurons. The Schratt lab through the use of siRNAs performed a functional screen on pre-selected circular RNAs to identify ones that regulate excitatory synaptogenesis in rat hippocampal neurons. They found seven circular RNAs that negatively regulate this process and studied one of them in more depth, and found out that it exerts its function by regulating the levels of a specific micro RNA. Their findings have been published in the article "A functional screen uncovers circular RNAs regulating excitatory synaptogenesis in hippocampal neurons" in Nature Communications.
Abstract
Circular RNAs (circRNAs) are an expanding class of largely unexplored RNAs which are prominently enriched in the mammalian brain. Here, we systematically interrogate their role in excitatory synaptogenesis of rat hippocampal neurons using RNA interference. Thereby, we identify seven circRNAs as negative regulators of excitatory synapse formation, many of which contain high-affinity microRNA binding sites. Knockdown of one of these candidates, circRERE, promotes the formation of electrophysiologically silent synapses. Mechanistically, circRERE knockdown results in a preferential upregulation of synaptic mRNAs containing binding sites for miR-128-3p. Overexpression of circRERE stabilizes miR-128-3p and rescues exaggerated synapse formation upon circRERE knockdown in a miR-128-3p binding site-specific manner. Overall, our results uncover circRERE-mediated stabilization of miR-128-3p as a means to restrict the formation of silent excitatory synaptic co-clusters and more generally implicate circRNA-dependent microRNA regulation in the control of synapse development and function.
Read the Publication in Nature Communications (Open Access)
Abstract, figure and title from Kelly et al. (2025) Nature Communications published under a CC BY 4.0 license.