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

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

doi:10.1016/j.celrep.2021.110282

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 invivo 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 invivo 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.

Highlights

Emerging data suggest the presence of significant alterations in cognitive flexibility, which is the ability to adjust one’s thoughts and behavior following changing circumstances, in patients with psychiatric disorders, such as bipolar disorder (BD) and schizophrenia (SCZ) (Leeson et al, 2009; O’Donnell et al, 2017; Waltz and Gold, 2007; Wegbreit et al, 2016)
Changes in relative HOMER1 mRNA isoform levels are differentially associated with deficits in circHomer1 expression In order to examine whether alterations in circHomer1 are associated with the expression of specific HOMER1 mRNA isoforms, we used isoform-specific quantitative real-time PCR in postmortem samples from the orbitofrontal cortex (OFC) of subjects with BD (n = 30), SCZ (n = 32), and unaffected controls (n = 33) derived from the Stanley Medical Research Institute (SMRI) (Tables S1 and S2; Torrey et al, 2000)
We quantified the expression of HOMER1A, a short activity-dependent, dominant-negative isoform produced from exons 1–5 and parts of intron 5; HOMER1B, the longest detected in human brain mRNA isoform composed of all nine exons; and HOMER1H, an intermediate in size and moderately expressed transcript produced by exons 1–5 and exon 9 (Figures 1A, 1B, and S1A–S1C)

Summary

Introduction

Emerging data suggest the presence of significant alterations in cognitive flexibility, which is the ability to adjust one’s thoughts and behavior following changing circumstances, in patients with psychiatric disorders, such as bipolar disorder (BD) and schizophrenia (SCZ) (Leeson et al, 2009; O’Donnell et al, 2017; Waltz and Gold, 2007; Wegbreit et al, 2016). Recent studies have suggested that different subsets of circRNAs could be differentially expressed in the frontal cortex of subjects with psychiatric disorders, such as BD and SCZ (Liu et al, 2019; Luykx et al, 2019; Mahmoudi et al, 2019; Zimmerman et al, 2020), while alterations in circRNA expression have been observed in the blood of patients with SCZ and unipolar depression (Yao et al, 2019; Zhang et al, 2020). Little is known about the role of psychiatric-disorder-associated circRNAs in the control of cognitive flexibility, as well as their interplay with protein-coding gene expression

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