The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

Abstract

Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

The Efficacy of Exercise to Attenuate Cocaine Relapse is Associated with Changes in Bdnf and Altered by Sex and Estrous Cycle Phase.

“…Work has also shown that site-specific infusion of Bdnf into the PFC during early abstinence, but not following protracted abstinence, attenuates subsequent cue-induced reinstatement responding (Berglind et al 2007) and normalizes neuroadaptations that are associated with the high levels of cocaine-seeking (Whitfield et al 2011). This idea of time-dependent upregulation of Bdnf is also supported by our current findings showing that when provided beginning during early abstinence, HDAC inhibition, which is known to increase Bdnf exon IV expression (Yasuda et al 2009), mimicked both the behavioral and molecular effects of wheel running. A caveat to this idea, however, is that wheel running did not increase Bdnf exon IV expression among saline controls.…”

“…Although NaBu is a non-specific HDAC inhibitor, and in this study its effects were examined following systemic administration, evidence suggests that inhibition of HDAC activity affects the expression of only approximately 2% of genes (Van Lint et al 1996;Davie et al 2003). Evidence also shows that Bdnf exon IV is activated in cortical regions including the PFC following systemic NaBu administration (Yasuda et al 2009), and that in the cortex, exon IV-dependent Bdnf transcription accounts for the majority of the neuronal activity-induced Bdnf expression (Tao et al 2002;Timmusk et al 1994). While these results provide support for the idea that epigenetic regulation of Bdnf likely mediates the efficacy of NaBu treatment, further work is needed to rule out other mechanisms (e.g., DAergic signaling).…”

“…Chromatin remodeling, including histone modifications and DNA methylation, and its influence on gene regulation, specifically regulation of the Bdnf gene, has become an increasing focus in drug addiction research Maze and Nestler, 2011;McQuown and Wood, 2011). (Yasuda et al 2009), decreases motivation for cocaine, cocaine-seeking, and cocaine-induced locomotor sensitization (Malvaez et al 2010;2013;Romieu et al 2011;Kennedy et al 2013). Further evidence supporting the hypothesis that altering histone acetylation may provide beneficial behavioral and molecular effects on cocaine-seeking will be presented in Chapter II of this dissertation.…”

“…A similar phenomenon is observed in animal models in which cocaine-seeking incubates over an abstinence period (Lu et al 2004). As in humans, this incubation effect is associated with a progressive increase in including Bdnf exon IV expression (Yasuda et al 2009). We hypothesized that wheel running would dose-dependently decrease subsequent cocaine-seeking, that its efficacy would be associated with changes in PFC Bdnf exon IV expression, and that the behavioral and molecular effects of exercise would be mimicked by NaBu.…”

Novel Protective Effects of Histone Deacetylase Inhibition on Stroke and White Matter Ischemic Injury

“…Brain-derived neurotrophic factor (BDNF) supports the survival of select differentiated neurons [32,33] and encourages the growth and differentiation of new neurons and synapses. Addition of VPA to cultured rat cortical neurons induces BDNF messenger RNA [34] and induces vascular endothelial growth factor, angiogenesis, and neurogenesis in vivo [35,36]. In a screen of small molecules structurally related to known HDAC inhibitors a compound referred to as crebinostat, for its ability to concomitantly activate cyclic adenosine monophosphate response element binding-mediated transcription, was identified [37].…”