Biomedical Sciences ETDs

Publication Date

Spring 2-15-2021

Abstract

Circular RNAs (circRNAs) are highly stable non-coding RNAs, derived from the covalent back-splicing of precursor mRNA molecules. Although circRNAs are highly enriched in the brain, the mechanism of action of brain expressed circRNAs and their relevance for psychiatric disorders remains largely unknown. Here we show that circHomer1, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from the Homer protein homolog 1 (HOMER1) gene, is significantly reduced in the prefrontal cortex and induced pluripotent stem-cell-derived neuronal cultures from patients with schizophrenia and bipolar disorder and is associated with the age of onset of schizophrenia. Furthermore, circHomer1 expression is inversely associated with Homer1b expression. In vivo circRNA-specific knockdown of circHomer1 in mouse orbitofrontal cortex resulted in increased synaptic expression of Homer1b and deficits in OFC-mediated cognitive flexibility, as well as differential expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. We then demonstrate that in vivo Homer1b-specific knockdown increases synaptic circHomer1 levels within the OFC and improves OFC-mediated behavioral flexibility. Importantly, we show that double circHomer1 and Homer1b in vivo co-knockdown results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. We demonstrate that circHomer1 is an experience-dependent circRNA that is significantly altered during chance reversal learning and that variability in its baseline expression is significantly inversely correlated to behavioral performance during chance reversal learning. Lastly, we show a direct RNA-RNA interaction between circHomer1 and Homer1b occurs near their RBP-binding sites which can lead to the inhibition of each other’s synaptic localization. Taken together, our data provides novel mechanistic insights into the importance of circRNAs in brain function and disease.

Keywords

RNA, Circular RNA, circRNA, Bipolar Disorder, Schizophrenia, Homer1

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Nikolaos Mellios

Second Committee Member

Nora Perrone-Bizzozero

Third Committee Member

Jonathan Brigman

Fourth Committee Member

Amy Gardiner

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