Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia

Wonodi, Ikwunga; Hong, L. Elliot; Stine, O. Colin; Mitchell, Braxton D.; Elliott, Amie; Roberts, Rosalinda C.; Conley, Robert R.; McMahon, Robert P.; Thaker, Gunvant K.

doi:10.1002/ajmg.b.30811

Cited by 26 publications

(28 citation statements)

References 44 publications

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“…First, while the DAT is most strongly expressed in the striatum, it is also reliably found in extrastriatal regions (Ciliax et al, 1999;Saba et al, 2007), with evidence of genotype dependence in the frontal cortex (Wonodi et al, 2009). This observation opens up the possibility that these extrastriatal DATs may have a role in the pharmacogenetic effects observed here, especially given previous observations of SLC6A3-related differences in the activity of cortical regions during working memory, memory recognition, and response inhibition (Bertolino et al, 2006(Bertolino et al, , 2009Congdon et al, 2009).…”

Section: Pharmacogenetic Findingssupporting

confidence: 62%

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

Kasparbauer

Rujescu²,

Riedel

et al. 2014

Neuropsychopharmacol

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We pharmacologically challenged catecholamine reuptake, using methylphenidate, to investigate its effects on brain activity during a motor response inhibition task as a function of the 3 0 -UTR variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) gene (SLC6A3) and the availability of DATs in the striatum. We measured the cerebral hemodynamic response of 50 healthy males during a Go/No-Go task, a measure of cognitive control, under the influence of 40 mg methylphenidate and placebo using 3T functional magnetic resonance imaging. Subjects were grouped into 9-repeat (9R) carriers and 10/10 homozygotes on the basis of the SLC6A3 VNTR. During successful no-go trials compared with oddball trials, methylphenidate induced an increase of blood oxygen level-dependent (BOLD) signal for carriers of the SLC6A3 9R allele but a decrease in 10/10 homozygotes in a thalamocortical network. The same pattern was observed in caudate and inferior frontal gyrus when successful no-go trials were compared with successful go trials. We additionally investigated in a subset of 35 participants whether baseline striatal DAT availability, ascertained with 123 I-FP-CIT single photon emission computed tomography, predicted the amount of methylphenidate-induced change in hemodynamic response or behavior. Striatal DAT availability was nominally greater in 9R carriers compared with 10/10 homozygotes (d ¼ 0.40), in line with metaanalyses, but did not predict BOLD or behavioral changes following MPH administration. We conclude that the effects of acute MPH administration on brain activation are dependent on DAT genotype, with 9R carriers showing enhanced BOLD following administration of a prodopaminergic compound.

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Section: Pharmacogenetic Findingssupporting

confidence: 62%

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

Kasparbauer

Rujescu²,

Riedel

et al. 2014

Neuropsychopharmacol

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“…This finding qualifies the only previous report on a possible association by Wonodi et al (2009). In the context of a clinical study on schizophrenia patients, they found a significant link between the polymorphism and predictive pursuit in their healthy control group.…”

Section: Discussionsupporting

confidence: 86%

“…In contrast, visually driven pursuit did not systematically vary across individuals. Previous studies that strived to investigate the role of dopamine in different pursuit processes used continuous waveform motion, providing perfectly predictable target trajectories, and blanked the target for a short period during ongoing pursuit (Thaker et al, 2004; Wonodi et al, 2009). Although this approach has yielded seminal insights into pursuit deficits in schizophrenia patients, we suggest that using two separate paradigms for visually guided and anticipatory pursuit allows a more detailed differentiation between underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…However, the link between both polymorphisms and individual variations in pursuit has not been investigated appropriately yet. Studies focused primarily on pursuit deficits in schizophrenic patients (Rybakowski et al, 2002; Thaker et al, 2004; Haraldsson et al, 2009; Wonodi et al, 2009). Although healthy subjects were included as control groups, procedures might have been not well suited to detect individual differences in the normal range and particularly in different pursuit parameters.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Dopamine in Anticipatory Pursuit Eye Movements: Insights from Genetic Polymorphisms in Healthy Adults

Billino

Hennig

Gegenfurtner

2016

eNeuro

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There is a long history of eye movement research in patients with psychiatric diseases for which dysfunctions of neurotransmission are considered to be the major pathologic mechanism. However, neuromodulation of oculomotor control is still hardly understood. We aimed to investigate in particular the impact of dopamine on smooth pursuit eye movements. Systematic variability in dopaminergic transmission due to genetic polymorphisms in healthy subjects offers a noninvasive opportunity to determine functional associations. We measured smooth pursuit in 110 healthy subjects genotyped for two well-documented polymorphisms, the COMT Val158Met polymorphism and the SLC6A3 3′-UTR-VNTR polymorphism. Pursuit paradigms were chosen to particularly assess the ability of the pursuit system to initiate tracking when target motion onset is blanked, reflecting the impact of extraretinal signals. In contrast, when following a fully visible target sensory, retinal signals are available. Our results highlight the crucial functional role of dopamine for anticipatory, but not for sensory-driven, pursuit processes. We found the COMT Val158Met polymorphism specifically associated with anticipatory pursuit parameters, emphasizing the dominant impact of prefrontal dopamine activity on complex oculomotor control. In contrast, modulation of striatal dopamine activity by the SLC6A3 3′-UTR-VNTR polymorphism had no significant functional effect. Though often neglected so far, individual differences in healthy subjects provide a promising approach to uncovering functional mechanisms and can be used as a bridge to understanding deficits in patients.

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“…We genotyped rs2275163C>T and rs1053230C>T (Table 2), using TaqMan technology as previously described (Wonodi et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia

Wonodi

McMahon

Krishna

et al. 2014

Schizophrenia Research

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Background Cognitive deficits compromise quality of life and productivity for individuals with schizophrenia and have no effective treatments. Preclinical data point to the kynurenine pathway of tryptophan metabolism as a potential target for pro-cognitive drug development. We have previously demonstrated association of a kynurenine 3-monooxygenase (KMO) gene variant with reduced KMO gene expression in postmortem schizophrenia cortex, and neurocognitive endophenotypic deficits in a clinical sample. KMO encodes kynurenine 3-monooxygenase (KMO), the rate-limiting microglial enzyme of cortical kynurenine metabolism. Aberration of the KMO gene might be the proximal cause of impaired cortical kynurenine metabolism observed in schizophrenia. However, the relationship between KMO variation and cognitive function in schizophrenia is unknown. This study examined the effects of the KMO rs2275163C>T C (risk) allele on cognitive function in schizophrenia. Methods We examined the association of KMO polymorphisms with general neuropsychological performance and P50 gating in a sample of 150 schizophrenia and 95 healthy controls. Results Consistent with our original report, the KMO rs2275163C>T C (risk) allele was associated with deficits in general neuropsychological performance, and this effect was more marked in schizophrenia compared with controls. Additionally, the C (Arg452) allele of the missense rs1053230C>T variant (KMO Arg452Cys) showed a trend effect on cognitive function. Neither variant affected P50 gating. Conclusions These data suggest that KMO variation influences a range of cognitive domains known to predict functional outcome. Extensive molecular characterization of this gene would elucidate its role in cognitive function with implications for vertical integration with basic discovery.

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Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia

Cited by 26 publications

References 44 publications

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

The Role of Dopamine in Anticipatory Pursuit Eye Movements: Insights from Genetic Polymorphisms in Healthy Adults

Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia

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