# Unraveling the biogenesis and molecular mechanisms of a neuronal-enriched circRNA altered in psychiatric disease

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2022 · $569,195

## Abstract

PROJECT SUMMARY
Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their
potential involvement in brain function and psychiatric disease. Following unbiased circRNA profiling and
validation in multiple postmortem brain cohorts, we have uncovered that circHomer1, a neuronal-enriched
circRNA abundantly expressed in the adult frontal cortex, is significantly reduced in the prefrontal cortex of
subjects with psychiatric disease. Our preliminary data suggest that circHomer1 can inhibit the synaptic
localization of the long Homer1b mRNA isoform within the orbitofrontal cortex (OFC), by competing for binding
to the RNA-binding protein (RBP) HuD, a known regulator of neuronal mRNA trafficking. Moreover, our pilot
data suggest that circHomer1 can influence glutamatergic synaptic transmission and that restoring Homer1b
levels in the OFC can rescue the alterations in cognitive flexibility observed following circHomer1 knockdown
(KD). We propose to determine the mechanisms by which circHomer1 regulates the synaptic localization of
Homer1b (Aim 1), to examine the role of Homer1b in circHomer1-mediated alterations in neuronal function and
cognitive flexibility (Aim 2), and to identify novel upstream regulators of human neuronal circHomer1
biogenesis (Aim3). Our central hypothesis is that RBPs bind near the circHomer1 splice junction to promote its
biogenesis within neurons and that circHomer1 can sequester HuD from binding to Homer1b, thereby inhibiting
Homer1b synaptic localization and disrupting neuronal activity and OFC function. The rationale of the proposed
research is that elucidating the unexplored role of synaptic plasticity-regulating circRNAs will uncover novel
molecular mechanistic insights into the nature of neuronal function disturbances related to psychiatric disease.
For this proposal we first intend to generate circHomer1 knockout (KO) mice via CRISPR-mediated deletion of
antisense intronic regions required for circHomer1 backsplicing and examine the impact on synaptic Homer1b
expression, as well as determine whether competition for HuD binding between circHomer1 and Homer1b is
responsible for the increased Homer1b synaptic localization as a result of loss of circHomer1 (Aim 1). We will
then examine the importance of altered Homer1b levels for neuronal activity and OFC function (Aim 2). Finally,
using a novel circRNA sensor approach together with genome editing in mouse cortical neurons and iPSC-
derived neuronal cultures we will uncover upstream regulators of neuronal circHomer1 biogenesis (Aim 3). The
following three specific aims will attempt to address our hypotheses: 1) Test the hypothesis that circHomer1
inhibits Homer1b mRNA synaptic localization via competing for binding to HuD within the OFC. 2) Test the
hypothesis that Homer1b OE is sufficient to impair OFC function and that normalizing its expression following
circHomer1 loss can restore neuronal activity and OFC-mediated cognitive flexi...

## Key facts

- **NIH application ID:** 10365415
- **Project number:** 1R01MH125899-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Nikolaos Mellios
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $569,195
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365415

## Citation

> US National Institutes of Health, RePORTER application 10365415, Unraveling the biogenesis and molecular mechanisms of a neuronal-enriched circRNA altered in psychiatric disease (1R01MH125899-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10365415. Licensed CC0.

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