ArticleNeurobiology of disease2016
The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex.
Article in Neurobiology of disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Novel dopamine 4 receptor ligands differentially ameliorate ADHD-like behaviors in spontaneously hypertensive rats.Psychopharmacology · 2026Article
- Stimulation of Dopamine D4 Receptors in the Nucleus Accumbens Shell Increases Palatable Food Intake in Satiated Male Rats: Modulation by NMDA and AMPA Receptors.Brain sciences · 2024Article
- Serine racemase deletion alters adolescent social behavior and whole-brain cFos activation.Frontiers in psychiatry · 2024Article
- The mesocortical dopaminergic system cannot explain hyperactivity in an animal model of attention deficit hyperactivity disorder (ADHD)- Spontaneously hypertensive rats (SHR).Laboratory animal research · 2023Article
- Molecular Mechanisms Underlying NMDARs Dysfunction and Their Role in ADHD Pathogenesis.International journal of molecular sciences · 2023Review
- Breviscapine Ameliorates Fear Extinction and Anxiety in BALB/cJ Mice.Psychiatry investigation · 2023Article
- Protein quality control ofFrontiers in cellular neuroscience · 2022Review
- Attention-deficit/hyperactive disorder updates.Frontiers in molecular neuroscience · 2022Review
- Functional and pharmacological role of the dopamine DFrontiers in endocrinology · 2022Review
- Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications.Molecular psychiatry · 2022Review
- DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors.Cerebral cortex (New York, N.Y. : 1991) · 2021Article
- Attention Networks in ADHD Adults after Working Memory Training with a DualBrain sciences · 2020Article
- Methylation-related metabolic effects of D4 dopamine receptor expression and activation.Translational psychiatry · 2019Article
- Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission.Schizophrenia bulletin · 2019Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
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Abstract
The human dopamine D4 receptor (hD4R) variants with long tandem repeats in the third intracellular loop have been strongly associated with attention deficit hyperactivity disorder (ADHD) and risk taking behaviors. To understand the potential molecular mechanism underlying the connection, we have investigated the synaptic function of human D4R polymorphism by virally expressing the ADHD-linked 7-repeat allele, hD4.7, or its normal counterpart, hD4.4, in the prefrontal cortex (PFC) of D4R knockout mice. We found that hD4R bound to the SH3 domain of PSD-95 in a state-dependent manner. Activation of hD4.7 caused more reduction of NR1/PSD-95 binding and NR1 surface expression than hD4.4 in PFC slices. Moreover, the NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSC) in PFC pyramidal neurons were suppressed to a larger extent by hD4.7 than hD4.4 activation. Direct stimulation of NMDARs with the partial agonist d-cycloserine prevented the NMDAR hypofunction induced by hD4.7 activation. Moreover, hD4.7-expressing mice exhibited the increased exploratory and novelty seeking behaviors, mimicking the phenotypic hallmark of human ADHD. d-cycloserine administration ameliorated the ADHD-like behaviors in hD4.7-expressing mice. Our results suggest that over-suppression of NMDAR function may underlie the role of hD4.7 in ADHD, and enhancing NMDAR signaling may be a viable therapeutic strategy to ADHD humans carrying the D4.7 allele.
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