Theses Doctoral

Modulation of Sleep by the Adhesion G Protein-Coupled Receptor ADGRL3 in Drosophila

Coie, Lilian Alana

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 latrophilin 3 (ADGRL3) have been associated with an increased risk for attention deficit hyperactivity disorder (ADHD) and substance use disorder (SUD) in various linkage and association studies. Disrupting the function of ADGRL3 homologs across mammalian and invertebrate model systems leads to changes in various dopaminergic phenotypes such as hyperactivity, sleep impairment, and changes in sensitivity to psychostimulants, suggesting that ADGRL3 contributes to behavior by modulating dopamine signaling. Here, I use behavioral and imaging studies to delineate an important role for Cirl, the Drosophila homolog of ADGRL3, in a recently characterized dopaminergic sleep circuit.

Sleep impairment is a common symptom in both SUD and ADHD, and sleep studies are well established in Drosophila. Our work shows that fruit flies that carry a null mutation for Cirl are hyperactive and display a deficit in sleep that is enhanced by adult thermogenetic activation of dopamine neurons. Though Cirl displays high expression within dopamine neurons, conditional knockout of Cirl in dopamine neurons does not recapitulate sleep deficits seen in Cirl null flies, and specific rescue of Cirl in a knockout background does not ameliorate them. Intriguingly, activating dopamine neurons in Cirl null flies throughout development rescued the sleep deficits, indicating that this dopaminergic intervention induces lasting changes that can ameliorate lack of Cirl function.

Imaging studies reveal that Cirl shows high expression in the central complex, which is involved in sleep and receives dense dopaminergic input. I demonstrate that Cirl functions within different populations of the central complex downstream of dopaminergic innervation to differentially affect night and daytime sleep through both dopaminergic and non-dopaminergic mechanisms. This work delineates a novel role for an adhesion GPCR in modulating sleep behavior, and further characterizes ADGRL3 as a potential therapeutic target for disorders characterized by dysregulation of dopaminergic neurotransmission.


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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Javitch, Jonathan A.
Ph.D., Columbia University
Published Here
February 21, 2024