# Psychiatric disease-associated circRNA modulates synaptic efficacy and cortical function.

> **NIH NIH F31** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $37,556

## Abstract

Project Summary
Schizophrenia (SCZ) and Bipolar Disorder (BD) are multifactorial psychiatric disorders that are often marked by
impaired functioning of the prefrontal cortex (PFC) that leads to behavioral deficits including impairments in
executive functioning, such as cognitive flexibility. SCZ and BD have also been shown to have strong genetic
components linking the diseases to protein-coding genes, specifically those associated with synaptic
transmission and plasticity. Recently, circular RNAs (circRNAs) and other non-coding RNAs have been posited
to regulate genes leading to network changes and altered functional output. Although circular RNAs are highly
enriched in the mammalian brain, little is known about their functions and interactions with protein-coding genes.
Our recent work demonstrates that circHomer1, a circRNA derived from the post-synaptic density gene
HOMER1, is reduced in postmortem orbitofrontal cortex (OFC) samples from patients with SCZ and BD and is
inversely correlated to the relative abundance of HOMER1B, a long mRNA isoform associated with neuronal
hyperexcitability. Further, in vivo circHomer1 knockdown in mouse OFC increases the synaptic localization of
Homer1b and in mouse neuronal cultures, loss of circHomer1 increases neuronal excitability. Preliminary data
shows that loss of circHomer1 negatively impacts behavior. Mice with reduced circHomer1 expression in the
OFC exhibit significant learning impairments on reversal of a learned association, similar to those seen in patients
with psychiatric disorders. This project seeks to understand the mechanism of these alterations, by first testing
whether circHomer1 dynamically regulates the expression of Homer1 isoforms during behavior. Next, we will
test the hypothesis that reduction of aberrantly increased Homer1b after circHomer1 knockdown is sufficient to
rescue reversal impairment. We will then utilize in vivo electrophysiology during reversal learning to determine
whether synchronous neuronal activity within the OFC is disrupted. Finally, we will then test the hypothesis that
increased excitability after loss of circHomer1 alters spike-field coupling during the reversal learning paradigm.
The completion of these aims will help elucidate the mechanisms by which a circular RNA regulates mRNA
expression and localization to impact neuronal activity associated with behavioral flexibility and will provide
targets for future therapeutic applications for schizophrenia and bipolar disorder.

## Key facts

- **NIH application ID:** 9992759
- **Project number:** 1F31MH122121-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Amber J Zimmerman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,556
- **Award type:** 1
- **Project period:** 2020-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992759

## Citation

> US National Institutes of Health, RePORTER application 9992759, Psychiatric disease-associated circRNA modulates synaptic efficacy and cortical function. (1F31MH122121-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9992759. Licensed CC0.

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