A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

Alexander K. Hafez, Amber J. Zimmerman, Grigorios Papageorgiou, Jayapriya Chandrasekaran, Stephen K. Amoah, Rixing Lin, Evelyn Lozano, Caroline Pierotti, Michela Dell'Orco, Brigham J. Hartley, Begüm Alural, Jasmin Lalonde, John Matthew Esposito, Sabina Berretta, Alessio Squassina, Caterina Chillotti, Georgios Voloudakis, Zhiping Shao, John F. Fullard, Kristen J. BrennandGustavo Turecki, Panos Roussos, Roy H. Perlis, Stephen J. Haggarty, Nora Perrone-Bizzozero, Jonathan L. Brigman, Nikolaos Mellios

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA 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 circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b-specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-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 circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease.

Original languageEnglish
Article number110282
JournalCell Reports
Volume38
Issue number3
DOIs
StatePublished - 18 Jan 2022

Keywords

  • Homer1
  • OFC
  • bipolar disorder
  • circHomer1
  • circRNAs
  • cognitive flexibility
  • reversal learning

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