title: The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex.
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.
authors.affiliation: Dept. of Physiology & Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Luye
authors.initials: L
authors.lastname: Qin
authors.affiliation: Dept. of Physiology & Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA; School of Life Science, Zhaoqing University, Zhaoqing 526061, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liu
authors.affiliation: Dept. of Physiology & Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Ma
authors.affiliation: Dept. of Physiology & Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Dept. of Physiology & Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.affiliation: The MRC Centre for Synaptic Plasticity, University of Bristol Whitson, Bristol, UK.
authors.forename: Kei
authors.initials: K
authors.lastname: Cho
authors.affiliation: Dept. of Physiology & Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA. Electronic address: zhenyan@buffalo.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D006801:Humans; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000378:metabolism*; D017966:Pyramidal Cells / Q000502:physiology; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C493599:DRD4 protein, human; C493600:Drd4 protein, mouse; D050638:Receptors, Dopamine D4
keywords: Attention deficit hyperactivity disorder; Human dopamine D4 receptor; NMDA receptor; Novelty seeking behaviors; PSD-95; Polymorphism