Abstract
Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.
Highlights
Our results, which were corrected for various postmortem brain demographics such as RNA integrity number (RIN), postmortem interval (PMI), brain pH, and refrigeration interval (RI) using a general linear model, revealed robust reductions in circHomer1a, an exonic circRNA generated from HOMER1, in bipolar disorder (BD) as shown in the array, and in SCZ (Fig. 1d)
We provide novel evidence that circHomer1a, a highly expressed, neuronal-enriched, and evolutionary conserved circRNA originating from HOMER1, a gene known to regulate neuronal excitability and synaptic plasticity and linked to psychiatric disorders, is reduced in the orbitofrontal cortex (OFC) and stem cellderived neuronal cultures of both BD and SCZ patients
We show that circHomer1a levels are reduced in the dorsolateral prefrontal cortex (DLPFC) of subjects with SCZ and that changes in circHomer1a in both DLPFC and OFC are significantly positively correlated with the age of onset of SCZ
Summary
These authors contributed equally: Amber J. Zimmerman, Alexander K. Hafez, Stephen K. Amoah Supplementary information The online version of this article (https:// doi.org/10.1038/s41380-020-0653-4) contains supplementary material, which is available to authorized users. Bipolar disorder (BD) and schizophrenia (SCZ) are multifactorial and heterogeneous psychiatric disorders with an average age of onset during late adolescence to young adulthood that together affect more than 3.5% of the US population and result in significant socioeconomic burdens [1–3]. While many studies have uncovered critical protein-coding genes
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