A brain-enriched circular RNA controls excitatory neurotransmission and restricts sensitivity to aversive stimuli
Sebastián A. Giusti, Natalia S. Pino, Camila Pannunzio, Mora B. Ogando, Natalia G. Armando, Lillian Garrett, Annemarie Zimprich, Lore Becker, Maria L. Gimeno, Jerónimo Lukin, Florencia Merino, M. Belén Pardi, Olivia Pedroncini, G Mauro, Valerie Gailus Durner, Helmut Fuchs, Martin Hrabě de Angelis, Inés Lucía Patop, Christoph W. Turck, Jan M. Deussing, Daniela M. Vogt Weisenhorn, Olaf Jahn, Sebastián Kadener, Sabine M. Hölter, Nils Brose, Florian Giesert, Wolfgang Wurst, Antonia Marín‐Burgin, Damián Refojo
Abstract
Circular RNAs (circRNAs) are a large class of noncoding RNAs. Despite the identification of thousands of circular transcripts, the biological significance of most of them remains unexplored, partly because of the lack of effective methods for generating loss-of-function animal models. In this study, we focused on circTulp4, an abundant circRNA derived from the Tulp4 gene that is enriched in the brain and synaptic compartments. By creating a circTulp4-deficient mouse model, in which we mutated the splice acceptor site responsible for generating circTulp4 without affecting the linear mRNA or protein levels, we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of excitatory neurotransmission and sensitivity to aversive stimuli. This study provides evidence that circRNAs can regulate biologically relevant functions in neurons, with modulatory effects at multiple levels of the phenotype, establishing a proof of principle for the regulatory role of circRNAs in neural processes.