ABSTRACT GPR37L1 is a recently deorphanized receptor belonging to the larger family of seven transmembrane receptors that couple through G-proteins to regulate numerous biological functions. Using an unbiased computational approach to probe its clinical significance, we identified a statistically significant association between human genetic variants in GPR37L1 and a clinical diagnosis of migraine in a large, unselected patient population. Our subsequent characterization of GPR37L1 receptors carrying human coding variants revealed robust signaling differences and further study of gene targeted mice lacking the receptor demonstrated some interesting behavioral features such as altered sex-dependent anxiety-like behavior, which is often associated with chronic migraine-like states. Altogether, the results from these complementary approaches and the restricted GPR37L1 expression in astrocytes, whose dysfunction promotes migraine-like pain, strongly support the hypothesis that GPR37L1 signaling plays a protective role in migraine. Here, we propose to dissect the novel role of GPR37L1 signaling in the neuropathology of this disorder through a concerted effort combining a wide range of complementary approaches to: 1) Assess GPR37L1 expression and localization in mice exposed to a chronic migraine-like state; 2) Address the impact of genetic GPR37L1 deletion on astrocyte modulation of neuronal activity; and 3) Examine the effects of genetic GPR37L1 deletion on a chronic migraine model that involves progressively increased measures of cephalic allodynia, photophobia and anxiety-like behavior associated with repeated systemic administration of exogenous CGRP in female and male mice. To accomplish these aims, we have assembled an investigative team with the interdisciplinary expertise to conduct the broad range of genetic, biochemical, electrophysiological, and behavioral approaches that are necessary for a full understanding of the contributions of GPR37L1 to chronic migraine. Altogether, we expect the results will show that altering the GPR37L1 signaling pathway produces astrocyte dysfunction that critically affects neuronal function(s), resulting in increased sensitivity to head pain triggers and other responses consistent with migraine. If validated, the demonstration that GPR37L1 activation is protective with respect to migraine may have broad implications for other neurological disorders.

PROJECT NARRATIVE Using a patient centered approach, our studies reveal a potential protective player that may influence one or more astrocyte functions critical for support of neuronal functions in the context of migraine. Accordingly, this proposal seeks to understand how the GPR37L1 signaling pathway conveys this protective function using an innovative combination of genetic, biochemical, electrophysiological, and animal modeling approaches. Ultimately, we expect the findings will identify new avenues for improving prevention and treatment of migraine, for which current medicines are inadequate for a large segment of the population.