Biomedical Sciences ETDs

Publication Date

Spring 5-14-2022

Abstract

There are currently only very few efficacious drug treatments for SCZ and BD, none of which target and improve cognitive symptoms. Thus, there is an emerging need to develop novel therapeutics targeting molecular pathways linked to cognitive function and antipsychotic treatment. Circular RNAs (circRNAs) are stable non-coding RNAs, derived from the covalent back-splicing of precursor mRNA molecules. CircHomer1is a neuronal-enriched, activity-dependent circRNA, derived from the precursor of the long HOMER1B mRNA isoform, which is abundantly expressed in the adult frontal cortex and significantly downregulated in the prefrontal cortex of subjects with psychosis. Even though its relevance to psychiatric disorders and its role in cognitive function and synaptic plasticity have been well-established by previous work from our lab, little is known about the molecular mechanisms that underlie circHomer1 biogenesis in response to neuronal activity and psychiatric drug treatment. Our data suggest that the RNA-binding proteins EIF4A3 and FUS positively regulate neuronal circHomer1 expression. Furthermore, we show in primary cortical neurons that transcription of Eif4a3 and Fus mRNA and circHomer1 biogenesis is regulated via the MEK/ERK and PKA/CREB pathways. We then demonstrate via both in vitro and in vivo studies that NMDA and mGluR5 receptors are upstream modulators of circHomer1 expression. Lastly, we report that in vivo D2R antagonism increases circHomer1expression, whereas 5HT2AR blockade reduces circHomer1 levels in multiple brain regions. As a result, administration of Olanzapine, a commonly prescribed second-generation antipsychotic that targets both 5HT2AR and D2R simultaneously, did not result in notable changes in circHomer1 expression. Taken together, this study allows us to gain novel insights into the molecular circuits that underlie circHomer1 biogenesis and to further elucidate the role of this circRNA in psychiatric disorders.

Keywords

circHomer1, cognition, NMDAR, mGluR5, atypical antipsychotics

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, MD, Ph.D.

Second Committee Member

Juan R Bustillo, MD

Third Committee Member

Amy S Gardiner, Ph.D.

Fourth Committee Member

David N Linserbardt, Ph.D.

Comments

I am filling an embargo for 2 years. I will have submitted the embargo document prior the 15th of April 2022.

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