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  Reduced glutamatergic metabolism in the anterior cingulate cortex in carriers of the Met-allele of the BDNF Val66Met polymorphism

Martens, L., Fensky, L., Colic, L., Li, M., Richter, A., Behnisch, G., et al. (2017). Reduced glutamatergic metabolism in the anterior cingulate cortex in carriers of the Met-allele of the BDNF Val66Met polymorphism. Poster presented at 30th European College Neuropsychopharmacology Congress (ECNP 2017), Paris, France.

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Martens, L, Author
Fensky, L, Author
Colic, L, Author
Li, M, Author
Richter, A, Author
Behnisch, G, Author
Schott, B, Author
Seidenbecher, C, Author
Walter, M1, Author              
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1Universität Tübingen, ou_persistent22              

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 Abstract: Background and aim: Brain-derived neurotrophic factor (BDNF), protein found in central nervous and peripheral system, is involved in neurogenesis, synaptogenesis, and both glutamatergic (Glu) and GABAergic neuronal signaling. It is expressed in hippocampus, basal forebrain and cortex, brain regions regulating higher cortical functions such as memory, or emotion processing. Dysregulation of BDNF expression was shown in psychiatric diseases in anterior cingulate cortex [1], of which the pregenual region (pgACC) is implicated in downregulation of the limbic system, and has an important role in affective disorders [2]. Furthermore, a single-nucleotide polymorphism Val66Met on the human BDNF gene was associated with a predisposition for depression [3]. Functionally, Val66Met lowers activity-dependent secretion of BDNF [4], and consequentially affects glutamatergic neuron structure and functioning. Dysregulations in the glutamatergic system were also reported in affective disorders in the pgACC [5]. We therefore hypothesized that through the effects of BDNF on excitatory neuronal activity, Met carriers and Val/Val differ in their respective glutamatergic system and excitation/inhibitory balance in the pgACC. SNP effects were investigated in two independent healthy samples and scanner strengths, and controlled for possible confounding factors such as age and neuronal integrity. Methods: 31 healthy subjects (1 female, age = 29.45 ± 6.00) underwent a magnetic resonance spectroscopy (MRS) session at 3T. Proton MRS spectra were acquired in the bilateral pgACC. Combined levels of glutamate and glutamine (Glx) were assessed using a PRESS sequence. In the 7T sample, 100 healthy subjects (40 females, age = 26.79 ± 6.50) underwent a MRS measurement using a STEAM sequence in the same region. Subjects were genotyped for polymorphism at the Val66Met locus on the gene coding for BDNF (3T sample: 12 Met carriers (MC), 19 Val homozygotes (VH); 7T sample: 28 MC, 71 VH). For both samples, we performed an analysis of covariance on Glx/NAA with BDNF genotype (VH or MC) as factor, controlling for age, sex, and gray matter proportion in the MRS voxel. In the 7T sample, exploratory analyses of covariance were conducted on Glu/NAA and GABA/Glu to further characterize the influence of BDNF genotype on excitation/inhibition balance in the pgACC. Results: In the 3T sample, we found a significant effect of BDNF genotype (p = 0.025, F(1,22) = 5.78), where Met carriers had a decreased Glx/NAA ratio in the pgACC. We were able to replicate this finding within a larger sample at 7T (p = 0.034, F (1,93) = 4.651). Exploratory analyses on the 7T data showed a statistically non-significant trend toward reduced Glu/NAA levels (p = 0.11, F(1,93) = 2.772) and a significantly higher ratio of GABA/Glu (p = 0.01, F(1,89) = 6.822) in the pgACC of Met carriers compared to Val homozygotes. Conclusion: For the first time, we report an effect of the BDNF Val66Met polymorphism on glutamatergic metabolism in the pgACC across different scanners and field strengths. These robust findings, combined with previous research showing reduced glutamatergic metabolism in the pgACC of MDD patients [5] imply the Val66Met genotype as a potential risk factor for mood regulation disorders.

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 Dates: 2017-09
 Publication Status: Published in print
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 Identifiers: DOI: 10.1016/S0924-977X(17)30965-3
BibTex Citekey: MartensFCLRBSSW2017
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Title: 30th European College Neuropsychopharmacology Congress (ECNP 2017)
Place of Event: Paris, France
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Title: European Neuropsychopharmacology
Source Genre: Journal
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Pages: - Volume / Issue: 27 (Supplement 4) Sequence Number: - Start / End Page: S591 - S592 Identifier: -