Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus.
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.
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010862:Pilocarpine; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D018091:Receptors, AMPA; D010862:Pilocarpine; D006655:Histone Deacetylases; C104722:glutamate receptor ionotropic, AMPA 2