Synaptic protein dysfunction alters neuronal communication and is a likely cause of neuropsychiatric diseases, generally termed ‘synaptopathies’. Attention-deficit/hyperactivity disorder (ADHD) is a likely example of a synaptopathy, affecting 5-7% of children worldwide. The causes of ADHD are unknown and research on treatments suffers from a dearth of animal models. Our recent genetic analysis on C1ql3 knockout mice revealed phenotypes of hyperactivity, sleeping disturbances, and a deficit in forming emotional memories, all characteristic of ADHD. This constellation of phenotypes suggests C1ql3 knockout mice may be a novel ADHD animal model, distinct from current research and human treatments which focus on monoamines. This proposal will investigate the hypothesis that the synapse-promoting and behavior-regulating activity of C1QL3 is mediated by binding to a G protein-coupled receptor called BAI3. We will first show that the ligand/receptor pair co-localize at brain synapses, then biochemically map the binding interface. Using this information, we will create a BAI3 binding-deficient mutant form of C1QL3 that fails to rescue the ADHD-like phenotypes in C1ql3 knockout mice, demonstrating the importance of C1QL3-BAI3 interaction. This research is significant because it will elucidate the cause of the behavioral abnormalities in C1ql3 knockout mice and form the etiological and biochemical foundation for subsequent research on ADHD as a synaptopathy involving this new pathway. Our proposed research is innovative because the discovery of a novel ligand/receptor pair will reveal an entirely new biochemical pathway that can be potentially manipulated for therapeutic benefit in ADHD. Our proposal will open the door to design agonists to target the C1QL3-BAI3 interface as a potential therapy for ADHD.