Strengths and limitations of genetic models of ADHD
Abstract
The cause and pathophysiology of attention-deficit hyperactivity disorder (ADHD) are unknown, but compelling evidence suggests an involvement of genetic factors. While dopamine is believed to play a major role in ADHD, the role for norepinephrine and serotonin systems has also been indicated. Mutant mice are valuable tools to dissect the contribution of specific neurotransmitter systems to brain dysfunction and particularly useful to decode complex multi-transmitter interaction that is critical to the pathophysiology of ADHD. Genetically altered mice provided also an opportunity to test experimentally the role of novel candidate genes for this disorder identified in genetic clinical studies. While it is clear that no rodent model would be able to recapitulate fully the complex nature of ADHD, certain endophenotypes could be reasonably well mimicked in these models. Multiple studies have reported associations between polymorphisms in dopamine transporter (DAT) gene and ADHD. Although the functional consequences of these associations are still unclear, it is believed that alterations in DAT-mediated processes might contribute to the pathogenesis of ADHD. Mice lacking the dopamine transporter have elevated dopaminergic tone and represent a genetic animal model in which certain endophenotypes of ADHD can be recapitulated. These mutants as well as other mouse models of DAT dysfunction provided an opportunity to investigate the neuronal circuitry and molecular mechanisms involved in the inhibitory action of psychostimulants on hyperactivity. Several additional knockout and transgenic mouse models have been proposed to model ADHD. Strengths and limitations of currently available genetic mouse models of ADHD are discussed.
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In DAT knockout mice, DA is cleared very slowly from the synaptic cleft, causing a five fold elevation of extracellular DA in the striatum, a hyperdopaminergic state.
“In DAT knockout mice, DA is cleared very slowly from the synaptic cleft, causing a five fold elevation of extracellular DA in the striatum (that is, a hyperdopaminergic state).”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [443]
DAT knockout mice have been suggested to model ADHD because they are hyperactive, have reduced extinction of responses in food reinforcement operant tasks, and have impaired learning and memory.
“DAT knockout mice have been suggested to model ADHD because they are hyperactive ([443,444]), have reduced extinction of responses in food reinforcement operant tasks [445], and also have impaired learning and memory [444,446].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [443]
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Gerlach, M., Grünblatt, E., & Lange, K. W. (2013) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-013-0105-y · Cited by 18 · see citing works
- Authors
- Gainetdinov, R. R.
- Affiliations
- Italian Institute of Technology (IT)
- Corresponding author
- Gainetdinov, Raul R.
- ORCID
- Gainetdinov, Raul R.
- Venue
- ADHD Attention Deficit and Hyperactivity Disorders
- Published
- 2010-03
- Volume
- 2
- Issue
- 1
- Pages
- 21-30
- ISSN
- 1866-6116 (ISSN-L)
- 1866-6647
- OpenAlex
- W2168965542
- Cited by
- 24
- References
- 11
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 1 · 2020: 2 · 2017: 3 · 2016: 2 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- ADHD Attention Deficit and Hyperactivity Disorders (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- attention deficit hyperactivity disorder, genetic animal models, dopamine transporter, dopamine, norepinephrine, serotonin, knockout mice, transgenic mice, endophenotypes, neurotransmitter interactions, candidate genes
- MeSH terms
- Animals, Attention Deficit Disorder with Hyperactivity, Disease Models, Animal, Humans, Mice, Transgenic, Models, Genetic, Mice, Knockout, Dopamine Plasma Membrane Transport Proteins, Mice, Endophenotypes
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