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: 8.93). 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 Bookmarks
 · 
84 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; · 8.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: B cell CLL/lymphoma 2 protein, bcl-2, is an important anti-apoptotic factor that has been implicated in lithium's neuroprotective effect. However, most studies have focused on assessing the effects of lithium in neurons, ignoring examination of bcl-2 in astrocytes, which also influence neuronal survival and are affected in bipolar disorder. The aim of this study was to evaluate whether chronic lithium treatment also elevates bcl-2 expression in astrocytes compared with neuronal and mixed neuron-astrocyte cultures. Methods: Rat primary astrocyte, neuronal, and mixed neuron-astrocyte cultures were prepared from the cerebral cortices of 18-day embryos. The cell cultures were treated with lithium (1 mM) or vehicle for 24 h or 7 days. Thereafter, bcl-2 mRNA and protein levels were determined by RT-PCR and ELISA, respectively. Results: Chronic, but not acute, lithium treatment significantly increased bcl-2 protein levels in the astrocyte cultures compared with the vehicle-treated cultures. While lithium treatment increased bcl-2 protein levels in both neuronal and mixed neuron-astrocyte cultures, the elevations fell short of statistical significance compared with the respective vehicle-treated cultures. However, neither acute nor chronic lithium treatment affected bcl-2 mRNA levels in any of the three cell types studied. Conclusion: Increased bcl-2 levels in rat primary astrocyte cultures following chronic lithium treatment suggest astrocytes are also a target of lithium's action. In light of the evidence showing decreased numbers of glial cells in the post-mortem brain of patients bipolar disorder with and increased glial numbers following lithium treatment, the findings of this study indicate that lithium's action on astrocytes may account, at least in part, for its therapeutic effects in bipolar disorder.
    Iranian Journal of Medical Sciences 09/2013; 38(3):255-62.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM) volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female) with a mean age of 56.2±22.0 years (range: 21-92). Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P<.001). Moreover, the downward slope was steeper among the Bcl-2 rs956572 A-allele carriers than in the G-homozygous participants. Our data provide convergent evidence for the genetic effect of the Bcl-2 functional allelic variant in brain aging. The rs956572 G-allele, which is associated with significantly higher Bcl-2 protein expression and diminished cellular sensitivity to stress-induced apoptosis, conferred a protective effect against age-related changes in brain GM volume, particularly in the cerebellum.
    PLoS ONE 01/2013; 8(2):e56663. · 3.73 Impact Factor

Full-text (2 Sources)

View
19 Downloads
Available from
Jun 5, 2014