Genetic liability underlying reward-related comorbidity in psychiatric disorders involves the coincident functions of autism-linked ADGRL1 and hevin

Comorbidity between psychiatric traits is thought to involve overlapping pleiotropic effects from sets of genes. Notably, substance abuse is a shared comorbid condition among various neurodevelopmental disorders with externalizing symptoms such as autism spectrum disorder and attention-deficit hyperactivity disorder, thus hinting at the nucleus accumbens (NAc) as a site for predisposition underlying convergence of genetic influences in reward-related comorbidity. Here, we identify the autism-related gene encoding the adhesion G protein-coupled receptor (aGPCR) Latrophilin-1/ADGRL1 as an essential transducer of reward mechanisms in the NAc. We found that ADGRL1 mRNA is ubiquitously expressed throughout major NAc neuronal populations in mice. A mouse model of pan-neuronal Adgrl1 deficiency in the NAc displayed cocaine-seeking impairments in adult individuals denoting its role in drug-induced reinforcement and reward. Connecting molecular pathways of cocaine-induced learning, we uncover that ADGRL1 constitutes a functional receptor for autism-related cocaine effector molecule hevin/SPARCL1. Indeed, hevin interacts with membrane-expressed ADGRL1 and induces its internalization while stabilizing its uncleaved fraction. Moreover, hevin alters the formation of intercellular adhesion contacts mediated by ADGRL1 and Neurexin-1. Importantly, the functional constitutive coupling between ADGRL1 and various G protein pathways is selectively modulated by hevin stimulation with a bias toward Gi3, Gs, and G13 proteins. These findings unveil the dual role of ADGRL1 and hevin as genetic risk factors for both psychiatric disorders and substance abuse to define the molecular etiology of comorbidity.