A brain-enriched circular RNA controls excitatory neurotransmission and restricts sensitivity to aversive stimuli

GIUSTI SA,; PINO NS,; PANNUNZIO C, ; OGANDO, MORA B.; ARMANDO N; GARRET L; ZIMPRICH A; BECKER L ; GIMENO ML; LUKIN J; MERINO F; PARDI MB; PEDRONCINI, OLIVIA; DI MAURO GC; GAILUS DURNER V; FUCHS H; HRABE DE ANGELIS M; PATOP IL; TURCK CW; DEUSSING JM,; VOGT WEISENHORN DM; JAHN O; KADENER S; HOELTER SM, ; BROSE N, ; GIESERT F; WURST W; MARIN-BURGIN A; REFOJO D,

Science Advances

Science Advances is the American Association for the Advancement of Science

Año: 2024

2375-2548

Circular RNAs are a large class of non-coding RNAs present in all eukaryotic taxa. Despite47 the identification of thousands of circular transcripts, the biological significance of most of48 them remains largely unexplored, partly due to the lack of effective methods for generating49 loss-of-function animal models. In this study, we focused on circTulp4, a highly abundant50 circRNA that is enriched in the brain and synaptic compartments. By creating a circTulp4-51 deficient mouse model, in which we mutated the splice acceptor site responsible for52 generating circTulp4 without affecting the corresponding linear mRNA or protein levels,53 we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that54 circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of55 excitatory neurotransmission and sensitivity to aversive stimuli. This study provides56 compelling evidence that circRNAs can regulate biologically relevant functions in neurons,57 with modulatory effects at multiple levels of the phenotype, establishing a proof-of58 principle for the regulatory role of circRNAs in neural processes.