A bidirectional competitive interaction between circHomer1and Homer1bwithin the orbitofrontal cortex regulates reversal learning

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1is inversely associated with relative HOMER1BmRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1bmRNA. Furthermore, we show that circHomer1directly binds to Homer1bmRNA and that Homer1b-specific KD increases synaptic circHomer1levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1and Homer1b in vivoco-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease.