Altered Histone Acetylation atGlutamate Receptor 2andBrain-Derived Neurotrophic FactorGenes Is an Early Event Triggered by Status Epilepticus

Abstract

The mechanisms underlying seizure-induced changes in gene expression are unclear. Using a chromatin immunoprecipitation assay, we found that acetylation of histone H4 in rat hippocampal CA3 neurons was reduced at the glutamate receptor 2 (GluR2; GRIA2) glutamate receptor promoter but increased at brain-derived neurotrophic factor promoter P2 as soon as 3 hr after induction of status epilepticus by pilocarpine. This result indicates that status epilepticus rapidly activates different signal pathways to modulate histone acetylation in a promoter-specific manner. H4 deacetylation preceded seizure-induced GluR2 mRNA downregulation. The histone deacetylase inhibitor trichostatin A prevented and quickly reversed deacetylation of GluR2-associated histones. Trichostatin A also blunted seizure-induced downregulation of GluR2 mRNA in CA3. Thus, rapid gene-specific changes in histone acetylation patterns may be a key early step in the pathological processes triggered by status epilepticus.

Epigenetic Mechanisms in Stroke and Epilepsy

“…Alterations in expression of these proteins contribute to the pathophysiology of recurrent seizures. Administration of the HDAC inhibitor TSA to rats before induction of seizures prevented and rapidly reversed the increase in histone deacetylation at the gria2 promoter and blunted the downregulation of GluA2 (Huang et al, 2002). These findings link epigenetic remodeling to seizure-induced silencing of GluA2 and, indirectly, seizure-induced neuronal death.…”

“…A follow-up study by Dingledine and colleagues using a related animal model of status epilepticus, showed that seizures promote deacetylation of core histone protein H4 (a mark of gene repression) at the RE1 site of the gria2 promoter (gene encoding the AMPAR subunit GluA2), while promoting an increase in acetylation of H4 (a mark of open chromatin and active gene transcription) at the promoter of brain-derived neurotrophic factor BDNF (Huang et al, 2002;Tsankova et al, 2004). Although GluA2 expression was decreased, leading to an increase in GluA2-lacking, Ca 2 + -permeable AMPARs at CA3 synapses and neuronal death in CA3 Sanchez et al, 2001;Huang et al, 2002), BDNF expression was increased (Kokaia et al, 1995;Binder et al, 1999;Huang et al, 2002;Tsankova et al, 2004). Alterations in expression of these proteins contribute to the pathophysiology of recurrent seizures.…”

“…In pre-clinical studies, four main classes of HDAC are under investigation: the short-chain fatty acids, such as sodium butyrate, phenylbutyrate, and valproic acid, the hyroxamic acids, such as TSA and SAHA, the epoxyketones, such as trapoxin, and the benzamides (Abel and Zukin, 2008). SAHA and TSA promote neuronal survival in animal models of ischemia (Gibson and Murphy, 2010;Baltan et al, 2011b;Wang et al, 2012;Noh et al, 2012) and epilepsy (Huang et al, 2002;Kobow and Blumcke, 2011). Intriguingly, valproic acid, which is commonly prescribed as an anticonvulsant drug, was subsequently discovered to be an HDAC inhibitor (Gottlicher et al, 2001).…”

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…Thus, epigenetic marking of the genome can be considered a persistent form of cellular memory by which terminally differentiated cells remember their phenotype. In the past 10 years, different laboratories have reported that histone modifications (acetylation and methylation) and DNA methylation are regulated in adult neurons in association with learning and memory processes (for review, see Roth and Sweatt, 2009;Gupta el al., 2010), as well as in response to seizure (Huang et al, 2002;Tsankova et al, 2004) and psychotropic drugs (Li et al, 2004;Kumar et al, 2005) and in mental disorders (Levenson and Sweatt, 2005). These data suggest that epigenetic regulation also have a critical role in the postmitotic cells function.…”

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

“…In this context, it has been reported that status epilepticus-induced BDNF upregulation in the brain of rats is accompanied by hyperacetylation of histone H4 of the BDNF promoters. 43 Moreover, chronic cocaine-induced activation of BDNF promoters in rat brain is associated with histone H3 hyperacetylation. 44 On the other hand, BDNF promoter IV binds the transcriptional repressor, MeCP2 (a methyl-CpG-binding domain protein), in complex with the corepressor sin3a and HDACs.…”