title: Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction.
abstract: The LPHN3 gene has been associated with both attention deficit-hyperactivity disorder (ADHD) and addiction, suggesting that it may play a role in the etiology of these disorders. Unfortunately, almost nothing is known about the normal functions of this gene, which has hampered understanding of its potential pathogenic role. To begin to characterize such normal functions, we utilized a gene-trap embryonic stem cell line to generate mice mutant for the Lphn3 gene. We evaluated differential gene expression in whole mouse brain between mutant and wild type male littermates at postnatal day 0 using TaqMan gene expression assays. Most notably, we found changes in dopamine and serotonin receptors and transporters (Dat1, Drd4, 5Htt, 5Ht2a), changes in neurotransmitter metabolism genes (Th, Gad1), as well as changes in neural developmental genes (Nurr, Ncam). When mice were examined at 4-6 weeks of age, null mutants showed increased levels of dopamine and serotonin in the dorsal striatum. Finally, null mutant mice had a hyperactive phenotype in the open field test, independent of sex, and were more sensitive to the locomotor stimulant effects of cocaine. Considered together, these results suggest that Lphn3 plays a role in development and/or regulation of monoamine signaling. Given the central role for monoamines in ADHD and addiction, it seems likely that the influence of LPHN3 genotype on these disorders is mediated through alterations in monoamine signaling.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station 77843-3474, USA. dwallis@tamu.edu
authors.forename: Deeann
authors.initials: D
authors.lastname: Wallis
authors.forename: Denise S
authors.initials: DS
authors.lastname: Hill
authors.forename: Ian A
authors.initials: IA
authors.lastname: Mendez
authors.forename: Louise C
authors.initials: LC
authors.lastname: Abbott
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wellman
authors.forename: Barry
authors.initials: B
authors.lastname: Setlow
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016739:Behavior, Addictive / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D003042:Cocaine / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics*; D018000:Receptors, Peptide / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C513284:ADGRL3 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D003042:Cocaine