Adgrl3, also known as latrophilin 3 or LPHN3, is an adhesion G protein-coupled receptor. It is involved in various biological processes, especially those related to early neurodevelopment. Given its role in the central nervous system development, genetic models are valuable for studying its functions and implications in related disorders [1,4].

In zebrafish, adgrl3.1 -deficient models show externalizing behaviors such as hyperactivity, impulsivity, risk-taking, and attentional deficits. These phenotypes are rescued by atomoxetine, indicating noradrenergic mediation of adgrl3.1's externalizing effects. Transcriptomic analyses also reveal differentially expressed genes and enriched gene clusters, suggesting new functional pathways underlying externalizing-disorder-related behaviors [3].

In human studies, meta-analysis shows that certain Adgrl3 polymorphisms (rs6551665, rs1947274, rs1947275, rs2345039) are associated with childhood ADHD susceptibility, but not significantly with adult ADHD. Also, Adgrl3 variants can predict substance use disorder, and the rs4860437 variant is the predominant predictive one. Additionally, the rs6551665 variant of Adgrl3 is associated with both early-onset ADHD and Autism Spectrum Disorder (ASD) susceptibility, suggesting it might be part of a shared vulnerability factor for these neurodevelopmental disorders [1,2,4].

In conclusion, Adgrl3 plays a crucial role in early neurodevelopment. Model-based research, such as the zebrafish adgrl3.1 -deficient model, has revealed its functions in externalizing-disorder-related behaviors and associated pathways. In humans, its polymorphisms are linked to childhood ADHD, substance use disorder, and ASD, highlighting its significance in understanding the pathophysiology of these neurodevelopmental and psychiatric disorders.