Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning

Abstract

Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit–specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches.

Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users

“…Moreover, we went one step further by showing that environmental factors (such as cocaine use) are able to moderate the direction of the polymorphism effects. This finding is especially interesting considering the conflicting results of previous studies suggesting that the effects of the 5-HTTLPR might be task specific (Anderson et al, 2012;Zilles et al, 2012). However, we were able to demonstrate consistent genotype effects across WM tasks measuring spatial (SWM), verbal (LNST), and visuospatial (PAL) WM subdomains (see Table 1 and Supplementary Figure S2).…”

“…However, results of the genetic studies are inconsistent. Some authors found the long allele of 5-HTTLPR to be associated with superior WM performance (Bosia et al, 2010;Zilles et al, 2012), whereas others claimed the short allele to be associated with improved performance (Enge et al, 2011;Anderson et al, 2012). It was argued that these conflicting results may either be due to a task specificity of the 5-HTTLPR (Anderson et al, 2012;Zilles et al, 2012) or due to undetected and moderating environmental factors (Zilles et al, 2012).…”

“…These effects are assumed to be mediated by 5-HT 2A and 5-HT 1A receptors in the PFC (Williams et al, 2002;Puig and Gulledge, 2011). Moreover, in genetic studies, the length polymorphism (short vs long allele) in the promoter region of the serotonin transporter (5-HTT) gene (5-HTTLPR and SLC6A4) and more recently a single-nucleotide polymorphism (SNP,rs4570625) in the promoter region of the tryptophan hydroxylase-2 (TPH2) gene have been found to influence WM performance (Reuter et al, 2008;Bosia et al, 2010;Homberg and Lesch, 2011;Zilles et al, 2012). This is plausible because the 5-HTT terminates 5-HT from the synaptic cleft by 5-HT reuptake after synaptic signaling (Lesch et al, 1996;Glatz et al, 2003) and the TPH2 (the ratelimiting enzyme of 5-HT synthesis) appears to facilitate 5-HT neurotransmission by increasing 5-HT availability (Kim et al, 2002).…”

“…As outlined above, polymorphisms in 5-HTT and TPH2 genes (Reuter et al, 2008;Bosia et al, 2010;Homberg and Lesch, 2011;Zilles et al, 2012) as well as chronic cocaine use (Müller and Homberg, 2015) are assumed to impact 5-HT neurotransmission. Given that the 5-HT system has been linked to WM performance (Porter et al, 2003;Allen et al, 2006), we hypothesized that 5-HTT and TPH2 polymorphisms interact with cocaine use regarding WM performance.…”

Post-mortem findings in mood disorders, nightmares and therapeutic approaches of psychiatric diseases

“…Due to preliminary evidence from pharmacological studies on verbal and visuospatial subcomponents of working memory (WM) being subject to differential neurotransmitter modulation, Zilles et al [4] genotyped 20 healthy controls and 80 patients with schizophrenia, BD, or obsessive-compulsive disorder with respect to the dopaminergic and serotonergic systems. While DAT genotype revealed a significant effect on visuospatial WM, and 5-HTT again a significant one on verbal WM task performance, COMT did not show an influence on either domain.…”