A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

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 OFCmediated 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 diseaseassociated circRNA that regulates synaptic gene expression and cognitive flexibility.

Dysregulation of circRNA Expression in the Peripheral Blood of Individuals With Schizophrenia and Bipolar Disorder

“…For example, dysregulated CDR1as altered miR-7 accessibility and its target genes, resulted in de cits in synaptic neurotransmission and abnormal brain function associated with psychiatric disorders [28]. circHomer1a, a neuronal-enriched circRNA associated with neural plasticity [27], is decreased in the prefrontal cortex (PFC) and stem cell-derived neuronal cultures from patients with SZ and BD [66]. Furthermore, circHomer1a expression levels in dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) were positively associated with the age of onset of schizophrenia [66].…”

The Secret Garden of Neuronal circRNAs

“…As a proof of concept, in the frontal cortex of schizophrenic human patients [75,101] and in ALS patients [102] a broad circRNA dysregulation has been observed. In general, disease-associated circRNAs are considered promising biomarkers of the disorder, since they can be measured in different biofluids such as peripheral blood and saliva [8,103].…”

“…Two recent studies provided new approaches to KD circRNAs in vivo in animal models [74,75]. Pamudurti et al generated a Drosophila-specific shRNA vector based on the miR-1 precursor, expressing siRNAs directed against the BSJ of selected circRNAs [74].…”

“…The shRNA expression is temporally and spatially controlled by means of the GAL4/UAS expression system. Similarly, Zimmermann et al achieved a region-specific KD of circHomer1a in the mouse brain by using an shRNA expressed under the human synapsin promoter from a lentiviral vector [75]. Both approaches have low off-target effects.…”

“…It should be pointed out that circRNAs with a well-established molecular function are currently the minority. Interestingly, circHomer1, a highly expressed circRNA in the mammalian brain, was found to be significantly reduced in the prefrontal cortex of psychiatric patients suffering from schizophrenia and bipolar disorder, and in a patient iPS-derived neuronal culture [75]. The in vitro KD of circHomer1 in the mouse prefrontal cortex strongly altered the AS of genes involved in synaptic plasticity and psychiatric diseases.…”