Article

Bcl-2 Polymorphism Influences Gray Matter Volume in the Ventral Striatum in Healthy Humans

Mood and Anxiety Disorders Program, National Institute of Mental Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Biological psychiatry (Impact Factor: 9.47). 07/2009; 66(8):804-7. DOI: 10.1016/j.biopsych.2009.05.025
Source: PubMed

ABSTRACT Bcl-2 is a major regulator of neural plasticity and cellular resilience. A single nucleotide polymorphism (SNP) in the Bcl-2 gene, Bcl-2 rs956572, significantly modulates the expression of Bcl-2 protein and cellular vulnerability to apoptosis. We tested the hypothesis that this SNP would modulate gray matter (GM) volume in the limbic-cortical-striatal-pallidal-thalamic circuitry that plays major roles in mood regulation.
Forty-seven healthy subjects participated in this study (30 A carriers, 17 G homozygotes). Neuromorphometric differences between G homozygotes and A carriers were investigated using optimized voxel-based morphometry (VBM). Statistical significance was set at p < .05, corrected for multiple comparisons.
A carriers showed less GM volume than G homozygotes in the left ventral striatum (p(corrected) < .05).
Genetic variation in the Bcl-2 gene modulates GM volume in areas known to play key roles in the neurobiology of reward processes and emotion regulation and in the pathophysiology of mood disorders. Thus, the findings from the current study are noteworthy insofar as they converge with preclinical findings that Bcl-2 functions to enhance neuronal viability and might indirectly extend this evidence to humans.

0 Followers
 · 
140 Views
  • Source
    [Show abstract] [Hide abstract]
    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 (Ca(2+)) 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 (1)H-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 cm(3)) (1)H-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 Ca(2+), 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.Neuropsychopharmacology advance online publication, 17 October 2012; doi:10.1038/npp.2012.203.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2012; DOI:10.1038/npp.2012.203 · 7.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Psychiatric disorders are common and complex and their precise biological underpinnings remain elusive. Multiple epidemiological, molecular, genetic and gene expression studies suggest that immune system dysfunction may contribute to the risk for developing psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder. However, the precise mechanisms by which inflammation-related events confer such risk are unclear. In this review, we examine the peripheral and central evidence for inflammation in psychiatric disorders and the potential molecular mechanisms implicated including inhibition of neurogenesis, apoptosis, the HPA-axis, the role of brain-derived neurotrophic factor and the interplay between the glutamatergic, dopaminergic and serotonergic neurotransmitter systems. KeywordsInflammation–Cytokines–Etiology–Psychiatric disorders–Neurotransmitter imbalance–Maternal infections–Apoptosis–Brain Derived Neurotrophic Factor–Hypothalamic Pituitary Adrenal Axis–Glutamate–Dopamine–Serotonin–Quinolinic acid–Kynurenic acid
    06/2011; 2(2):121-137. DOI:10.2478/s13380-011-0019-0