# Adhesion GPCR Cirl as a novel regulator of dopamine neurotransmission

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $46,752

## Abstract

PROJECT ABSTRACT/SUMARY
Adhesion G-protein coupled receptors (GPCRs) are the second largest class of GPCRs yet their functions and
ligands remain predominantly unidentified. Polymorphisms in the gene encoding the adhesion GPCR ADGRL3
have been associated with an increased risk for substance use disorder and attention deficit hyperactivity
disorder in various linkage and association studies. Disrupting the function of the ADGRL3 homologs leads to
hyperactivity in four different model systems – zebrafish, fruit flies, mice, and rats. In addition to hyperactivity,
ADGRL3 knockout mice have higher dopamine levels in forebrain motor regions as well as increased sensitivity
to the stimulant cocaine, which acts on the dopamine transporter. Together with dopamine’s established role in
mediating locomotion, these findings suggest that ADGRL3 contributes to behavior by modulating dopamine
signaling; however, a mechanistic link has yet to be established. The goal of this proposed research is to
investigate the synaptic mechanisms that underlie ADGRL3 function in dopaminergic circuits using
Drosophila as a model system. I have replicated the hyperactive phenotype in fruit flies that carry a null
mutation for the ADGRL3 homolog, Cirl. To directly assay the role of Cirl in neurotransmission, I activated
dopamine neurons acutely and found that Cirl null flies were much more sensitive to dopamine
neurotransmission. Intriguingly, activating dopamine neurons in Cirl null flies throughout development rescued
Cirl null hyperactivity to control levels, indicating that tonic dopamine neurotransmission during development
may compensate for lack of Cirl function. To test whether Cirl functions in dopamine neurons to modulate activity,
I reintroduced Cirl expression in dopamine neurons in the Cirl null background and instead found that this
exacerbated the hyperactive phenotype. Thus, the hyperactivity seen in Cirl null mutants is likely not mediated
by its absence from dopamine neurons, but rather in a separate population of neurons in which Cirl normally
acts to reduce activity. My imaging studies have revealed that Cirl is expressed post-synaptically throughout the
brain, and additionally localizes to the central complex which is involved in locomotion and motor planning and
receives dense dopaminergic input. This proposal aims to first identify the dopamine neuron or group of neurons
that induces hyperactivity when acutely activated, and identify their synaptic contacts in the central complex.
Once I have identified this circuit, I will use optogenetics, in combination with in vivo 2-photon imaging of
fluorescent biosensors to delineate the pre and postsynaptic changes in this circuit responsible for the
hyperactive response to dopamine neuron activation during adulthood, as well as the reversal of this phenotype
in Cirl null flies subjected to continuous dopamine neuron activation throughout development. These results will
delineate how an adhesion GPCR modulates do...

## Key facts

- **NIH application ID:** 10401313
- **Project number:** 5F31DA053811-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Lilian Coie
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401313

## Citation

> US National Institutes of Health, RePORTER application 10401313, Adhesion GPCR Cirl as a novel regulator of dopamine neurotransmission (5F31DA053811-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10401313. Licensed CC0.

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