Abstract
Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.
Highlights
Bipolar disorder, known as manic depression, is a severe mental illness affecting about 1% of the population and has multifaceted potential causes [1]
We provide evidence that chronic treatment of the common mood stabilizer, VPA, elicits robust induction of prostate apoptosis response-4 (Par-4), which significantly impacts DRD2-mediated signaling
The induction mechanism involves dynamic chromatin remodeling in the Par-4 promoter regions and indicates that part of the mood stabilizing efficacy of VPA is mediated by changes in DRD2-mediated signaling processes
Summary
Known as manic depression, is a severe mental illness affecting about 1% of the population and has multifaceted potential causes [1]. The acetylation states of histone octamers are determined by the relative activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs), which correlate with the expression level of target genes [8]. This remodeling of the chromatin structure in the promoter regions of genes related to mood control appears to be important for the efficacy of various antidepressants and mood stabilizers [6]. In this regard, HDAC inhibitors have gained significant attention for their potential use for the treatment of mood disorders [5,9]
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