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Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT.

ABSTRACT: Gamma-aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphisms (SNPs) in GAD1 previously associated with risk for schizophrenia or cognitive dysfunction and the val158met polymorphism in COMT in 116 healthy volunteers using proton magnetic resonance spectroscopy. Two of the GAD1 SNPs (rs1978340 (p=0.005) and rs769390 (p=0.004)) showed effects on GABA levels as did COMT val158met (p=0.04). We then tested three SNPs in GAD1 (rs1978340, rs11542313, and rs769390) for interaction with COMT val158met based on previous clinical results. In this model, rs11542313 and COMT val158met showed significant main effects (p=0.001 and 0.003, respectively) and a trend toward a significant interaction (p=0.05). Interestingly, GAD1 risk alleles for schizophrenia were associated with higher GABA/Cre, and Val-Val homozygotes had high GABA/Cre levels when on a GAD1 risk genotype background (N=6). These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.

SUBMITTER: Marenco S

PROVIDER: S-EPMC2891897 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT.

Marenco Stefano S Savostyanova Antonina A AA van der Veen Jan Willem JW Geramita Matthew M Stern Alexa A Barnett Alan S AS Kolachana Bhaskar B Radulescu Eugenia E Zhang Fengyu F Callicott Joseph H JH Straub Richard E RE Shen Jun J Weinberger Daniel R DR

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20100331 8

Gamma-aminobutyric acid (GABA)-ergic transmission is critical for normal cortical function and is likely abnormal in a variety of neuropsychiatric disorders. We tested the in vivo effects of variations in two genes implicated in GABA function on GABA concentrations in prefrontal cortex of living subjects: glutamic acid decarboxylase 1 (GAD1), which encodes GAD67, and catechol-o-methyltransferase (COMT), which regulates synaptic dopamine in the cortex. We studied six single nucleotide polymorphis ...[more]

PMID: 20357758

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Project description:Background and purposeExecutive function impairment, a slight but noticeable cognitive deficit in mild cognitive impairment (MCI) patients, is influenced by gamma-aminobutyric acid (GABA) levels. Reduced cognitive function is accompanied by thinning of the cerebral cortex, which has higher GABA levels than white matter. However, the relationships among GABA levels, cortical thickness, and executive function in MCI patients have not yet been elucidated. We investigated the relationships among GABA levels, cortical thickness, and executive function in MCI patients.MethodsIn this study, a total of 36 MCI patients and 36 sex-, age-, and education-matched healthy controls (HC) were recruited. But 33 MCI patients and 35 HC were included because of head motion or poor data quality for three MCI patients and one HC. The levels of gamma-aminobutyric acid plus relative to creatine (GABA+/Cr) and glutamate-glutamine relative to creatine (Glx/Cr) in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) were measured using the Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence. Metabolite ratios, cortical thickness, and executive function and their interrelationships were determined in the MCI and HC groups.ResultsPatients with MCI showed lower GABA+/Cr levels in the ACC and PCC. Combined levels of GABA+ and Glx in the ACC and GABA+ in the PCC showed good diagnostic efficacy for MCI (AUC: 0.82). But no differences in cortical thickness were found between the two groups. In the MCI group, lower GABA+/Cr level was correlated to worse performance on the digit span test backward, and the shape trail test-B. The cortical thickness was not associated with GABA+ levels and executive function in patients.ConclusionThese results implied that decreased GABA levels in the ACC and PCC had a critical role in the early diagnosis of impaired executive function of MCI. Therefore, GABA in the ACC and PCC could be a potential diagnostic marker of the executive function decline of MCI.

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Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT.

Publications

Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT.

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