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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Authors | Luye Qin, Wenhua Liu, Kaijie Ma, Jing Wei, Ping Zhong, Kei Cho, Zhen Yan |
Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 95
Pg. 194-203
(Nov 2016)
ISSN: 1095-953X [Electronic] United States |
PMID | 27475724
(Publication Type: Journal Article)
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Copyright | Copyright © 2016 Elsevier Inc. All rights reserved. |
Chemical References |
- DRD4 protein, human
- Drd4 protein, mouse
- Receptors, Dopamine D4
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Topics |
- Animals
- Attention Deficit Disorder with Hyperactivity
(metabolism)
- Excitatory Postsynaptic Potentials
(physiology)
- Exploratory Behavior
(physiology)
- Humans
- Mice, Knockout
- Patch-Clamp Techniques
(methods)
- Prefrontal Cortex
(metabolism)
- Pyramidal Cells
(physiology)
- Receptors, Dopamine D4
(metabolism)
- Signal Transduction
(physiology)
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