The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development
Abstract
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.
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GWAS have indicated genes playing a role in ADHD that could be linked to neuronal plasticity mechanisms or to deficiencies in synthesis or release of neurotransmitters, mainly DA, but also serotonin and NE.
“Genome-wide association studies (GWAS) have indicated genes playing a role in ADHD that could be linked to neuronal plasticity mechanisms (neuronal migration, cell adhesion and neuron proliferation) [61] or to deficiencies in the synthesis or release of neurotransmitters (NTs), mainly DA, but also serotonin and NE [56, 62].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [62]
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- Authors
- Lange, M., Norton, W., Coolen, M., Chaminade, M., Merker, S., Proft, F., Schmitt, A., Vernier, P., Lesch, K.-P., & Bally-Cuif, L.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of Würzburg (DE)
- Corresponding author
- Norton, W
- Venue
- Molecular Psychiatry
- Published
- 2012-04-17
- Volume
- 17
- Issue
- 9
- Pages
- 946-954
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1964871373
- Cited by
- 175
- References
- 9
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 15 · 2023: 6 · 2022: 18 · 2021: 12 · 2020: 13 · 2019: 19 · 2018: 14 · 2017: 8 · 2016: 16 · 2015: 12 · 2014: 9 · 2013: 8 · 2012: 6
- FWCI
- 7.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-08-CEXC-0001)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- attention deficit hyperactivity disorder, LPHN3, zebrafish, dopaminergic neuron development, ventral diencephalon, locomotor hyperactivity, impulsive behavior, methylphenidate, atomoxetine, adhesion G protein-coupled receptors, neurodevelopmental disorders
- MeSH terms
- Atomoxetine Hydrochloride, Animals, Attention Deficit Disorder with Hyperactivity, Diencephalon, Disease Models, Animal, Methylphenidate, Motor Activity, Nerve Degeneration, Propylamines, Zebrafish, Receptors, Peptide, Dopamine Uptake Inhibitors, Gene Knockdown Techniques, Molecular Imaging, Dopaminergic Neurons
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