Journal Article

The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development

Chaminade, M, Norton, W, Schmitt, A, Lange, M, Proft, F, Lesch, K-P, Coolen, M, Merker, S, Bally-Cuif, L, Vernier, P

2012

Overview

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/368/2430 / 631/378/340 / 631/45/612/194 / 692/699/476/1311 / Analysis / Animals / Atomoxetine Hydrochloride / Attention Deficit Disorder with Hyperactivity - drug therapy / Attention Deficit Disorder with Hyperactivity - genetics / Attention deficit disorders. Hyperactivity / Attention deficit hyperactivity disorder / Behavior / Behavioral Sciences / Biological and medical sciences / Biological Psychology / Child clinical studies / Danio rerio / Development and progression / Diencephalon / Diencephalon - growth & development / Diencephalon - pathology / Diencephalon - physiopathology / Disease Models, Animal / Dopamine / Dopamine receptors / Dopamine Uptake Inhibitors - pharmacology / Dopamine Uptake Inhibitors - therapeutic use / Dopaminergic Neurons - cytology / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - pathology / Etiology / Freshwater / Gene Knockdown Techniques - methods / Gene Knockdown Techniques - psychology / Gene mapping / Genes / Genetic aspects / Genotype & phenotype / Hyperactivity / Impulsive behavior / Impulsivity / Laboratories / Life Sciences / Linkage analysis / Locomotor activity / Medical sciences / Medicine / Medicine & Public Health / Methylphenidate / Methylphenidate - pharmacology / Methylphenidate - therapeutic use / Molecular Imaging - methods / Molecular Imaging - psychology / Motor Activity - drug effects / Motor Activity - genetics / Motor Activity - physiology / Nerve Degeneration - genetics / Nerve Degeneration - pathology / Neural coding / Neurobiology / Neurodevelopmental disorders / Neurons / Neurons and Cognition / Neurosciences / original-article / Pharmacotherapy / Phenotypes / Physiological aspects / Propylamines - pharmacology / Propylamines - therapeutic use / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Receptors, Peptide - genetics / Receptors, Peptide - physiology / Risk factors / Software / Zebrafish