10 research outputs found
Developmental exposure to bisphenol A alters expression and DNA methylation of Fkbp5, an important regulator of the stress response
Bisphenol A (BPA), an abundant endocrine disruptor, affects stress-responsiveness and related behaviors in children. In rats, perinatal BPA exposure modifies stress response in pubertal offspring via unknown mechanisms. Here we examined possible epigenetic modifications in the glucocorticoid receptor gene and its regulator Fkbp5 in hypothalamus and hippocampus of exposed offspring. We found increased DNA methylation of Fkbp5 and reduced protein levels in the hippocampus of exposed male rats. Similar effects were obtained in a male hippocampal cell line when exposed to BPA during differentiation. The estrogen receptor (ER) antagonist ICI 182,780 or ERÎČ knock-down affected Fkbp5 expression and methylation similarly to BPA. Further, BPA's effect on Fkbp5 was abolished upon knock-down of ERÎČ, suggesting a role for this receptor in mediating BPA's effects on Fkbp5. These data demonstrate that developmental BPA exposure modifies Fkbp5 methylation and expression in male rats, which may be related to its impact on stress responsiveness. © 2015 The Authors
Gabapentin increases expression of ÎŽ subunit-containing GABA A receptors
Background: Gabapentin is a structural analog of the inhibitory neurotransmitter Îł-aminobutyric acid (GABA). Its
anticonvulsant, analgesic and anxiolytic properties suggest that it increases GABAergic inhibition; however, the
molecular basis for these effects is unknownas gabapentin does not directlymodify GABA type A (GABAA) receptor
function, nor does itmodify synaptic inhibition. Here,we postulated that gabapentin increases expression of ÎŽ
subunit-containing GABAA (ÎŽGABAA) receptors that generate a tonic inhibitory conductance inmultiple brain regions
including the cerebellum and hippocampus.
Methods: Cell-surface biotinylation, Western blotting, electrophysiologic recordings, behavioral assays, highperformance
liquid chromatography and gas chromatography-mass spectrometry studies were performed
using mouse models.
Findings: Gabapentin enhanced expression of ÎŽGABAA receptors and increased a tonic inhibitory conductance in
neurons. This increased expression likely contributes to GABAergic effects as gabapentin caused ataxia and
anxiolysis in wild-type mice but not ÎŽ subunit null-mutant mice. In contrast, the antinociceptive properties of
gabapentin were observed in both genotypes. Levels of GABAA receptor agonists and neurosteroids in the
brain were not altered by gabapentin.
Interpretation: These results provide compelling evidence to account for the GABAergic properties of gabapentin.
Since reduced expression of ÎŽGABAA receptor occurs in several disorders, gabapentin may have much broader
therapeutic applications than is currently recognized