Bipolar disorder is a common and debilitating affective disorder, affecting approximately 1 percent of the population. While Lithium and valproic acid (VPA) usually provide effective therapy, each drug has significant risks and therapy is not always successful. The goal of this project is to apply basic research methods to the study of mental health in order to identify the molecular targets of VPA in the treatment of bipolar disorder. Identifying the molecular target of VPA should help in the development of safer and more effective therapies for bipolar disorder, and should also help to elucidate the molecular mechanisms underlying the pathogenesis of this disorder. VPA is also widely used as an anticonvulsant in diverse forms of epilepsy and is a potent teratogen in humans, yet the direct target is unknown in any of these settings. We have found that VPA potently inhibits histone deacetylase (HDAC; IC50 = 0.4mM), a critical regulator of gene expression that generally represses transcription. We have found that VPA mimics established HDAC inhibitors, such as trichostatin A (TSA), in their ability to activate transcription and that TSA mimics the teratogenic effects of VPA in vivo. VPA also mimics the effects of lithium on cultured cells by stimulating transcription of genes regulated by the wnt signaling pathway. However, these effects of VPA appear to be through inhibition of HDAC, in contrast to lithium, which acts through distinct targets. In this application, we propose to characterize further the biochemical mechanism of HDAC inhibition by VPA, test whether all classes of HDAC are inhibited by VPA, and examine the effect of other anticonvulsants, especially those with reported efficacy in bipolar disorder, on HDAC activity. We will also examine the effect of VPA on expression of endogenous genes regulated by HDACs in cultured neurons and in the mouse brain. A previously generated transgenic mouse line carrying a transcription reporter sensitive to VPA will be tested for in vivo response to VPA at the level of gene expression. These studies will form the basis for future work to test whether inhibition of HDAC plays a role in the clinical response to VPA therapy. Furthermore, identification of HDAC as a likely target for VPA induced teratogenesis should allow a direct in vitro test of teratogenic potential of VPA related compounds.
| O'Brien, W Timothy; Klein, Peter S (2007) Regulation of glycogen synthase kinase-3 in patients with affective disorders. Biol Psychiatry 61:139-41 |
| Gurvich, Nadia; Berman, Melissa G; Wittner, Ben S et al. (2005) Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo. FASEB J 19:1166-8 |
| Gurvich, Nadia; Tsygankova, Oxana M; Meinkoth, Judy L et al. (2004) Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 64:1079-86 |
