The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex

Qin, Luye; Liu, Wenhua; Ma, Kaijie; Wei, Jing; Zhong, Ping; Cho, Kei; Yan, Zhen

doi:10.1016/j.nbd.2016.07.024

Cited by 18 publications

(26 citation statements)

References 68 publications

(86 reference statements)

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“…[44][45][46][47][48] The ADHD-linked human dopamine D4 receptor variant induces over-suppression of NMDAR function and aberrant regulation of synchronous network activity in PFC. 49,50 Consistent with the general finding of our current study, it has been found that overstimulation of D4 receptors in the PFC induces dysregulation of emotions reminiscent to the effects observed in schizophrenia. [51][52][53] Moreover, disruption of D4 signaling in the PFC renders animals more sensitive to stress-related conditioning memories.…”

Section: Discussionsupporting

confidence: 92%

Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission

Tan

Wang

Williams

et al. 2018

Schizophrenia Bulletin

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A combination of genetic and environmental risk factors has been considered as the pathogenic cause for mental disorders including schizophrenia. Here, we sought to find out whether the abnormality of the dopamine system, coupled with the exposure to modest stress, is sufficient to trigger the manifestation of schizophrenia-like behaviors. We found that exposing dopamine D4 receptor knockout (D4KO) mice with 1-week restraint stress (2 h/d) induced significant deficits in sensorimotor gating, cognitive processes, social engagement, as well as the elevated exploratory behaviors, which are reminiscent to schizophrenia phenotypes. Electrophysiological studies found that GABAergic transmission was significantly reduced in prefrontal cortical neurons from stressed D4KO mice. Additionally, administration of diazepam, a GABA enhancer, restored GABAergic synaptic responses and ameliorated some behavioral abnormalities in stressed D4KO mice. These results have revealed that the combination of 2 key genetic and environmental susceptibility factors, dopamine dysfunction and stress, is a crucial trigger for schizophrenia-like phenotypes, and GABA system in the prefrontal cortex is a downstream convergent target that mediates some behavioral outcomes.

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Section: Discussionsupporting

confidence: 92%

Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission

Tan

Wang

Williams

et al. 2018

Schizophrenia Bulletin

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“…The different outcome of baseline mode on Conflict Effect between ADHD groups with and without medication might be explained by the effect of the stimulants [ 73 , 109 ]. The conflict (or executive control) network is mainly modulated by the dopamine system and involves brain structures in the prefrontal and anterior cingulate cortex, the anterior insula, and the basal ganglia [ 110 , 111 , 112 ]. It has been suggested that WMT might change the density of cortical dopamine receptors in the prefrontal cortex [ 113 , 114 , 115 ].…”

Section: Discussionmentioning

confidence: 99%

Attention Networks in ADHD Adults after Working Memory Training with a Dual n-Back Task

et al. 2020

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Patients affected by Attention-Deficit/Hyperactivity Disorder (ADHD) are characterized by impaired executive functioning and/or attention deficits. Our study aim is to determine whether the outcomes measured by the Attention Network Task (ANT), i.e., the reaction times (RTs) to specific target and cue conditions and alerting, orienting, and conflict (or executive control) effects are affected by cognitive training with a Dual n-back task. We considered three groups of young adult participants: ADHD patients without medication (ADHD), ADHD with medication (MADHD), and age/education-matched controls. Working memory training consisted of a daily practice of 20 blocks of Dual n-back task (approximately 30 min per day) for 20 days within one month. Participants of each group were randomly assigned into two subgroups, the first one with an adaptive mode of difficulty (adaptive training), while the second was blocked at the level 1 during the whole training phase (1-back task, baseline training). Alerting and orienting effects were not modified by working memory training. The dimensional analysis showed that after baseline training, the lesser the severity of the hyperactive-impulsive symptoms, the larger the improvement of reaction times on trials with high executive control/conflict demand (i.e., what is called Conflict Effect), irrespective of the participants’ group. In the categorical analysis, we observed the improvement in such Conflict Effect after the adaptive training in adult ADHD patients irrespective of their medication, but not in controls. The ex-Gaussian analysis of RT and RT variability showed that the improvement in the Conflict Effect correlated with a decrease in the proportion of extreme slow responses. The Dual n-back task in the adaptive mode offers as a promising candidate for a cognitive remediation of adult ADHD patients without pharmaceutical medication.

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“…This result is in contrast to inhibition of cAMP formation, where the D4.7R response to dopamine was reported to be less potent but equally efficacious. 16 Dopamine stimulation of MAP kinase phosphorylation, mediated by G protein signaling, was similar for D4.2R, D4.4R, and D4.7R, further indicating that PLM is a signaling response that differentiates the D4.7R from D4.2R and D4.4 subtypes.…”

Section: Resultsmentioning

confidence: 80%

“…14 A higher number of repeats implies that additional proteins can associate with the D4.7R, with the potential for more diverse signaling, although the additional protein interactions can restrict D4R access to phospholipids. The D4R is bound to postsynaptic scaffolding protein-95 (PSD-95) via SH3 domain-based binding, where it modulates N -methyl- d -aspartate (NMDA) receptor function in a VNTR-dependent manner, 16 raising the possibility that the D4R may modulate synaptic function via the influence of dopamine-stimulated PLM on proteins sharing its membrane environment.…”

Section: Introductionmentioning

confidence: 99%

“…Modest differences in G protein/effector coupling efficiency 15,17–19 and receptor heterodimerization 20,21 have been described among D4R VNTR variants, as well as greater inhibition of NMDA receptor function in the prefrontal cortex by the D4.7R. 16 However, the functional importance of D4R repeat number remains unclear and the influence of D4R VNTR on D4R-mediated PLM has not been previously investigated.…”

Section: Introductionmentioning

confidence: 99%

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Methylation-related metabolic effects of D4 dopamine receptor expression and activation

et al. 2019

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D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine synthase (MS). We evaluated the impact of D4R expression on folate-dependent phospholipid methylation (PLM) and MS activity, as well as cellular redox and methylation status, in transfected CHO cells expressing human D4R variants containing 2, 4, or 7 exon III repeats (D4.2R, D4.4R, D4.7R). Dopamine had no effect in non-transfected CHO cells, but increased PLM to a similar extent for both D4.2R- and D4.4R-expressing cells, while the maximal increase was for D4.7R was significantly lower. D4R expression in CHO cells decreased basal MS activity for all receptor subtypes and conferred dopamine-sensitive MS activity, which was greater with a higher number of repeats. Consistent with decreased MS activity, D4R expression decreased basal levels of methylation cycle intermediates methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), as well as cysteine and glutathione (GSH). Conversely, dopamine stimulation increased GSH, SAM, and the SAM/SAH ratio, which was associated with a more than 2-fold increase in global DNA methylation. Our findings illustrate a profound influence of D4R expression and activation on MS activity, coupled with the ability of dopamine to modulate cellular redox and methylation status. These previously unrecognized signaling activities of the D4R provide a unique link between neurotransmission and metabolism.

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The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex

Cited by 18 publications

References 68 publications

Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission

Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission

Attention Networks in ADHD Adults after Working Memory Training with a Dual n-Back Task

Methylation-related metabolic effects of D4 dopamine receptor expression and activation

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