title: Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction.
abstract: BACKGROUND
  The Latrophilin 3 (LPHN3) gene (recently renamed Adhesion G protein-coupled receptor L3 (ADGRL3)) has been linked to susceptibility to attention deficit/hyperactivity disorder (ADHD) and vulnerability to addiction. However, its role and function are not well understood as there are no known functional variants.
  
  
  METHODS
  To characterize the function of this little known gene, we phenotyped Lphn3 null mice. We assessed motivation for food reward and working memory via instrumental responding tasks, motor coordination via rotarod, and depressive-like behavior via forced swim. We also measured neurite outgrowth of primary hippocampal and cortical neuron cultures. Standard blood chemistries and blood counts were performed. Finally, we also evaluated the transcriptome in several brain regions.
  
  
  RESULTS
  Behaviorally, loss of Lphn3 increases both reward motivation and activity levels. Lphn3 null mice display significantly greater instrumental responding for food than wild-type mice, particularly under high response ratios, and swim incessantly during a forced swim assay. However, loss of Lphn3 does not interfere with working memory or motor coordination. Primary hippocampal and cortical neuron cultures demonstrate that null neurons display comparatively enhanced neurite outgrowth after 2 and 3 days in vitro. Standard blood chemistry panels reveal that nulls have low serum calcium levels. Finally, analysis of the transcriptome from prefrontal cortical, striatal, and hippocampal tissue at different developmental time points shows that loss of Lphn3 results in genotype-dependent differential gene expression (DGE), particularly for cell adhesion molecules and calcium signaling proteins. Much of the DGE is attenuated with age, and is consistent with the idea that ADHD is associated with delayed cortical maturation.
  
  
  CONCLUSIONS
  Transcriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with both ADHD and addiction phenotypes. The data should further motivate analyses of Lphn3 function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development.
authors.affiliation: Department of Psychiatry McKnight Brain Institute University of Florida College of Medicine Gainesville Florida 32610.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Orsini
authors.affiliation: Department of Psychiatry McKnight Brain Institute University of Florida College of Medicine Gainesville Florida 32610.
authors.forename: Barry
authors.initials: B
authors.lastname: Setlow
authors.affiliation: Department of Computer Science and Engineering Texas A&M University College Station Texas 77843.
authors.forename: Michael
authors.initials: M
authors.lastname: DeJesus
authors.affiliation: Department of Biochemistry and Biophysics Texas A&M University College Station Texas 77843.
authors.forename: Stacy
authors.initials: S
authors.lastname: Galaviz
authors.affiliation: Department of Biochemistry and Biophysics Texas A&M University College Station Texas 77843.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Loesch
authors.affiliation: Department of Computer Science and Engineering Texas A&M University College Station Texas 77843.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ioerger
authors.affiliation: Department of Biochemistry and Biophysics Texas A&M University College Station Texas 77843.
authors.forename: Deeann
authors.initials: D
authors.lastname: Wallis
keywords: ADHD; Lphn3/Adgrl3; SUD; behavior; calcium; cell adhesion; neurite outgrowth; transcriptome