Influences of COMT and 5-HTTLPR Polymorphisms on Cognitive Flexibility in Healthy Women: Inhibition of Prepotent Responses and Memory Updating

Weiss, Elisabeth M.; Schulter, Günter; Fink, Andréas; Reiser, Eva M.; Mittenecker, Erich; Niederstätter, Harald; Nagl, Simone; Parson, Walther; Papousek, Ilona

doi:10.1371/journal.pone.0085506

Cited by 24 publications

(20 citation statements)

References 83 publications

(4 reference statements)

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“…Interestingly, the s-allele of the 5-HTTLPR has also been associated with anxiety (Kenna et al, 2012 ) and cognitive deficits (Weiss et al, 2014 ), which are also prominent in patients with ASD, as mentioned above. Since prenatal valproate significantly affects serotonergic neurotransmission (Miyazaki et al, 2005 ; Oyabu et al, 2013 ), the present study investigates the potential interaction between valproate and a genetic reduction of the SERT.…”

Section: Introductionmentioning

confidence: 89%

Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

2016

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There is ample evidence that prenatal exposure to valproate (or valproic acid, VPA) enhances the risk of developing Autism Spectrum Disorders (ASD). In line with this, a single injection of VPA induces a multitude of ASD-like symptoms in animals, such as rats and mice. However, there is equally strong evidence that genetic factors contribute significantly to the risk of ASD and indeed, like most other psychiatric disorders, ASD is now generally thought to results from an interaction between genetic and environmental factors. Given that VPA significantly impacts on the serotonergic system, and serotonin has strong biochemical and genetic links to ASD, we aimed to investigate the interaction between genetic reduction in the serotonin transporter and prenatal valproate administration. More specifically, we exposed both wildtype (SERT+/+) rats and rats heterozygous for the serotonin transporter deletion (SERT+/−) to a single injection of 400 mg/kg VPA at gestational day (GD) 12. The offspring, in adulthood, was assessed in four different tests: Elevated Plus Maze and Novelty Suppressed Feeding as measures for anxiety and prepulse inhibition (PPI) and latent inhibition as measures for cognition and information processing. The results show that prenatal VPA significantly increased anxiety in both paradigm, reduced PPI and reduced conditioning in the latent inhibition paradigm. However, we failed to find a significant gene–environment interaction. We propose that this may be related to the timing of the VPA injection and suggest that whereas GD12 might be optimal for affecting normal rat, rats with a genetically compromised serotonergic system may be more sensitive to VPA at earlier time points during gestation. Overall our data are the first to investigate gene * environmental interactions in a genetic rat model for ASD and suggest that timing may be of crucial importance to the long-term outcome.

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Section: Introductionmentioning

confidence: 89%

Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

2016

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“…Similarly, the generalizability is limited primarily to individuals of Caucasian ethnicity; due to identified frequency differences in allele distribution among different ethnic groups, 19 , 37 it is important that this is examined in future studies as an additional moderator of the gender, 5-HTTLPR and age effect on neurocognition. Third, as is typical of candidate gene studies, 15 , 38 the effect size for the 5-HTTLPR × age × gender interaction was small, but it is unlikely that a single genetic polymorphism would have a large direct effect on cognitive phenotypes. Finally, the use of a replication cohort would be a significant strength to ensure that findings are not the result of methodological biases, but this was not feasible in the current study and should be considered an important limitation.…”

Section: Discussionmentioning

confidence: 96%

Association between the serotonin transporter gene polymorphism and verbal learning in older adults is moderated by gender

et al. 2017

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The S allele of the functional 5-HTTLPR polymorphism has previously been associated with reductions in memory function. Given the change in function of the serotonergic system in older adults, and the functional consequences of memory decline in this age group, further investigation into the impact of 5-HTTLPR in healthy older adults is required. This investigation examined the effect of 5-HTTLPR variants (S carriers versus L/L homozygotes) on verbal and visual episodic memory in 438 healthy older adults participating in the Tasmanian Healthy Brain Project (age range 50–79 years, M=60.35, s.d.=6.75). Direct effects of 5-HTTLPR on memory processes, in addition to indirect effects through interaction with age and gender, were assessed. Although no direct effects of 5-HTTLPR on memory processes were identified, our results indicated that gender significantly moderated the impact that 5-HTTLPR variants exerted on the relationship between age and verbal episodic memory function as assessed by the Rey Auditory Verbal Learning Test. No significant direct or indirect effects were identified in relation to visual memory performance. Overall, this investigation found evidence to suggest that 5-HTTLPR genotype affects the association of age and verbal episodic memory for males and females differently, with the predicted negative effect of S carriage present in males but not females. Such findings indicate a gender-dependent role for 5-HTTLPR in the verbal episodic memory system of healthy older adults.

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“…Additionally, in a decision making task where prefrontal cortical control is needed to overcome choice bias, s-carriers are more susceptible to bias and show decreased prefrontal cortical function measured with fMRI (Roiser et al, 2009). Finally, s-carriers have a decreased ability to monitor and update information in working memory (Weiss et al, 2014). Together, these studies suggest that genetic variation of the serotonin transporter gene is related to changes in executive function and support our hypothesis that the decreased mean ERP amplitude during hit trials in s-carriers in the right anterior superior ROI 1000–1500 ms post-stimulus presentation during source memory is related to cognitive control.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in the serotonin transporter gene influences ERP old/new effects during recognition memory

et al. 2015

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Recognition memory is defined as the ability to recognize a previously encountered stimulus and has been associated with spatially and temporally distinct event related potentials (ERPs). Allelic variations of the serotonin transporter gene (SLC6A4) have recently been shown to impact memory performance. Common variants of the serotonin transporter-linked polymorphic region (5HTTLPR) of the SLC6A4 gene result in long (l) and short (s) allelic variants with carriers of the s allele having lowered transcriptional efficiency. Thus, the current study examines the effects polymorphisms of the SLC6A4 gene have on performance and ERP amplitudes commonly associated with recognition memory. Electroencephalogram (EEG), genetic, and behavioral data were collected from sixty participants as they performed an item and source memory recognition task. In both tasks, participants studied and encoded 200 words, which were then mixed with 200 new words during retrieval. Participants were monitored with EEG during the retrieval portion of each memory task. EEG electrodes were grouped into four ROIs, left anterior superior, right anterior superior, left posterior superior, and right posterior superior. ERP mean amplitudes during hits in the item and source memory task were compared to correctly recognizing new items (correct rejections). Results show that s-carriers have decreased mean hit amplitudes in both the right anterior superior ROI 1000–1500 ms post stimulus during the source memory task and the left anterior superior ROI 300–500 ms post stimulus during the item memory task. These results suggest that individual differences due to genetic variation of the serotonin transporter gene influences recognition memory.

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Influences of COMT and 5-HTTLPR Polymorphisms on Cognitive Flexibility in Healthy Women: Inhibition of Prepotent Responses and Memory Updating

Cited by 24 publications

References 83 publications

Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

Association between the serotonin transporter gene polymorphism and verbal learning in older adults is moderated by gender

Genetic variation in the serotonin transporter gene influences ERP old/new effects during recognition memory

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