Adgrl3, also known as latrophilin 3 or LPHN3, is an adhesion G protein-coupled receptor. It plays a role in synapse formation in the hippocampus through a dual-pathway mechanism involving Gαs signalling activation and recruitment of postsynaptic protein scaffolds [5]. Alternative splicing of Adgrl3 controls its G-protein-coupling mode and synapse formation [5].

Genetic studies have associated Adgrl3 polymorphisms with various disorders. Meta-analysis shows that Adgrl3 variants are associated with childhood ADHD, but not significantly with adult ADHD [1]. In zebrafish, adgrl3.1-deficient models display externalizing behaviors like hyperactivity, impulsivity, and attentional deficits, which are rescued by atomoxetine, indicating noradrenergic mediation [3]. Also, Adgrl3 variants can predict substance use disorder (SUD) in ADHD participants, with rs4860437 being a predominant predictive variant [2]. Moreover, in a patient with recurrent ependymoma, Adgrl3 was consistently mutated during the disease process, and lower ADGRL3 mRNA levels were associated with shorter overall survival in ependymomas [4].

In conclusion, Adgrl3 is crucial for synapse formation. Model-based research, such as gene-knockout zebrafish and human genetic association studies, has revealed its role in neurodevelopmental disorders like ADHD and SUD, as well as in the evolution of ependymoma. Understanding Adgrl3 can potentially offer new insights into the pathophysiology of these diseases and guide treatment strategies.

References:

1. Bruxel, E M, Moreira-Maia, C R, Akutagava-Martins, G C, Rohde, L A, Hutz, M H. 2020. Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility. In Molecular psychiatry, 26, 2277-2285. doi:10.1038/s41380-020-0673-0. https://pubmed.ncbi.nlm.nih.gov/32051549/

2. Arcos-Burgos, Mauricio, Vélez, Jorge I, Martinez, Ariel F, Mastronardi, Claudio A, Muenke, Maximilian. 2019. ADGRL3 (LPHN3) variants predict substance use disorder. In Translational psychiatry, 9, 42. doi:10.1038/s41398-019-0396-7. https://pubmed.ncbi.nlm.nih.gov/30696812/

3. Fontana, Barbara D, Reichmann, Florian, Tilley, Ceinwen A, Norton, William H J, Parker, Matthew O. 2023. adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment. In Translational psychiatry, 13, 304. doi:10.1038/s41398-023-02601-4. https://pubmed.ncbi.nlm.nih.gov/37783687/

4. Wang, Jing, Xi, Shao-Yan, Zhao, Qi, Sai, Ke, Chen, Zhong-Ping. 2022. Driver mutations in ADGRL3 are involved in the evolution of ependymoma. In Laboratory investigation; a journal of technical methods and pathology, 102, 702-710. doi:10.1038/s41374-021-00721-3. https://pubmed.ncbi.nlm.nih.gov/35013530/

5. Wang, Shuai, DeLeon, Chelsea, Sun, Wenfei, Roth, Bryan L, Südhof, Thomas C. 2024. Alternative splicing of latrophilin-3 controls synapse formation. In Nature, 626, 128-135. doi:10.1038/s41586-023-06913-9. https://pubmed.ncbi.nlm.nih.gov/38233523/