Abstract
B-cell lymphoma 2 (Bcl-2) is an important regulator of cellular plasticity and resilience. In bipolar disorder (BD), studies have shown a key role for a Bcl-2 gene single-nucleotide polymorphism (SNP) rs956572 in the regulation of intracellular calcium (Ca2+) dynamics, Bcl-2 expression/levels, and vulnerability to cellular apoptosis. At the same time, Bcl-2 decreases glutamate (Glu) toxicity in neural cells. Abnormalities in Glu function have been implicated in BD. In magnetic resonance spectroscopy (MRS) studies, anterior cingulated cortex (ACC) Glu levels have been reported to be increased in bipolar depression and mania, but no study specifically evaluated ACC Glu levels in BD-euthymia. Here, we compared ACC Glu levels in BD-euthymia compared with healthy subjects using 1H-MRS and also evaluated the selective role of the rs956572 Bcl-2 SNP in modulating ACC Glu and Glx (sum of Glu and glutamine) in euthymic-BD. Forty euthymic subjects with BD type I and forty healthy controls aged 18–40 were evaluated. All participants were genotyped for Bcl-2 rs956572 and underwent a 3-Tesla brain magnetic resonance imaging examination including the acquisition of an in vivo PRESS single voxel (2 cm3) 1H-MRS sequence to obtain metabolite levels from the ACC. Euthymic-BD subjects had higher Glu/Cre (creatine) and Glx/Cre compared with healthy controls. The Bcl-2 SNP AA genotype was associated with elevated ACC Glu/Cre and Glx/Cre ratio in the BD group but not in controls. The present study reports for the first time an increase in ACC Glu/Cre and Glx/Cre ratios in BD-euthymia. Also, Bcl-2 AA genotype, previously associated with lower Bcl-2 expression and increase intracellular Ca2+, showed to be associated with increased ACC Glu and Glx levels in euthymic-BD subjects. The present findings reinforce a key role for glutamatergic system dysfunction in the pathophysiology of BD, potentially involving modulatory effects by Bcl-2 in the ACC.
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Acknowledgements
We would like to thank the members of Mood Disorders Unit (GRUDA) and Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo for their hard work, as well as the volunteers for their collaboration. We also thank Sao Paulo Research Foundation (Fapesp) and Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS). This study was financed by Sao Paulo Research Foundation (Fapesp). Dr Salvadore is a full time employee of Janssen pharmaceutical company. Dr Moreno has acted as a consultant to and conducted research sponsored by companies with developments in the area of bipolar and depressive disorders (Servier, BMS, Eli Lilly, Abbott, Astra Zêneca, GSK) and received research grants from Research Foundation Support Agency of the State of Sao Paulo, Brazil (FAPESP). Dr Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. Dr Zarate is also the recipient of the Brain & Behavior Research Foundation Award. Dr Machado-Vieira has received research grants from Research Foundation Support Agency of the State of Sao Paulo, Brazil (FAPESP). We declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service.
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Soeiro-de-Souza, M., Salvadore, G., Moreno, R. et al. Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder. Neuropsychopharmacol 38, 468–475 (2013). https://doi.org/10.1038/npp.2012.203
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DOI: https://doi.org/10.1038/npp.2012.203
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