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Frontoparietal cortical thickness mediates the effect of COMT Val158Met polymorphism on age-associated executive function.

ABSTRACT: Proper dopamine (DA) signaling is likely necessary for maintaining optimal cognitive performance as we age, particularly in prefrontal-parietal networks and in fronto-striatal networks. Thus, reduced DA availability is a salient risk factor for accelerated cognitive aging. A common polymorphism that affects DA D1 receptor dopamine availability, COMT Val158Met (rs4680), influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4-fold reduction in synaptic DA compared to COMT Met carriers. Furthermore, dopamine receptors and postsynaptic availability are drastically reduced with aging, as is executive function performance that ostensibly relies on these pathways. Here, we investigated in 176 individuals aged 20-94 years whether: (1) COMT Val carriers differ from their Met counterparts in thickness of regional cortices receiving D1 receptor pathways: prefrontal, parietal, cingulate cortices; (2) this gene-brain association differs across the adult lifespan; and (3) COMT-related regional thinning evidences cognitive consequences. We found that COMT Val carriers evidenced thinner cortex in prefrontal, parietal, and posterior cingulate cortices than COMT Met carriers and this effect was not age-dependent. Further, we demonstrate that thickness of these regions significantly mediates the effect of COMT genotype on an executive function composite measure. These results suggest that poorer executive function performance is due partly to thinner association cortex in dopaminergic-rich regions, and particularly so in individuals who are genetically predisposed to lower postsynaptic dopamine availability, regardless of age.

SUBMITTER: Miranda GG

PROVIDER: S-EPMC6251730 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Frontoparietal cortical thickness mediates the effect of COMT Val<sup>158</sup>Met polymorphism on age-associated executive function.

Miranda Giuseppe G GG Rodrigue Karen M KM Kennedy Kristen M KM

Neurobiology of aging 20180921

Proper dopamine (DA) signaling is likely necessary for maintaining optimal cognitive performance as we age, particularly in prefrontal-parietal networks and in fronto-striatal networks. Thus, reduced DA availability is a salient risk factor for accelerated cognitive aging. A common polymorphism that affects DA D1 receptor dopamine availability, COMT Val<sup>158</sup>Met (rs4680), influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4-fold reduction in synaptic DA compared ...[more]

PMID: 30342271

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Project description:Catechol-o-methyltransferase (COMT) is an enzyme that metabolizes catecholamines, and is crucial for clearance of dopamine (DA) in prefrontal cortex. Val158Met polymorphism, which causes a valine (Val) to methionine (Met) substitution at codon 158, is reported to be associated with human psychopathologies in some studies. The Val/Val variant of the enzyme results in higher dopamine metabolism, which results in reduced dopamine transmission. Thus, it is important to investigate the relation between Val158Met polymorphisms using rodent models of psychiatric symptoms, including negative symptoms such as motivational dysfunction. In the present study, humanized COMT transgenic mice with two genotype groups (Val/Val (Val) and Met/Met (Met) homozygotes) and wild-type (WT) mice from the S129 background were tested using a touchscreen effort-based choice paradigm. Mice were trained to choose between delivery of a preferred liquid diet that reinforced panel pressing on various fixed ratio (FR) schedules (high-effort alternative), vs. intake of pellets concurrently available in the chamber (low-effort alternative). Panel pressing requirements were controlled by varying the FR levels (FR1, 2, 4, 8, 16) in ascending and descending sequences across weeks of testing. All mice were able to acquire the initial touchscreen operant training, and there was an inverse relationship between the number of reinforcers delivered by panel pressing and pellet intake across different FR levels. There was a significant group x FR level interaction in the ascending limb, with panel presses in the Val group being significantly lower than the WT group in FR1-8, and lower than Met in FR4. These findings indicate that the humanized Val allele in mice modulates FR/pellet-choice performance, as marked by lower levels of panel pressing in the Val group when the ratio requirement was moderately high. These studies may contribute to the understanding of the role of COMT polymorphisms in negative symptoms such as motivational dysfunctions in schizophrenic patients.

Dataset Information

Frontoparietal cortical thickness mediates the effect of COMT Val158Met polymorphism on age-associated executive function.

Publications

Frontoparietal cortical thickness mediates the effect of COMT Val<sup>158</sup>Met polymorphism on age-associated executive function.

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