title: General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus.
abstract: Early postnatal exposure to general anesthesia (GA) may be detrimental to brain development, resulting in long-term cognitive impairments. Older literature suggests that in utero exposure of rodents to GA causes cognitive impairments in the first-generation as well as in the second-generation offspring never exposed to GA. Thus, the authors hypothesize that transient exposure to GA during critical stages of synaptogenesis causes epigenetic changes in chromatin with deleterious effects on transcription of target genes crucial for proper synapse formation and cognitive development. They focus on the effects of GA on histone acetyltransferase activity of cAMP-responsive element-binding protein and the histone-3 acetylation status in the promoters of the target genes brain-derived neurotrophic factor and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (c-Fos) known to regulate the development of neuronal morphology and function.
  
  
  
  Seven-day-old rat pups were exposed to a sedative dose of midazolam followed by combined nitrous oxide and isoflurane anesthesia for 6 h. Hippocampal neurons and organotypic hippocampal slices were cultured in vitro and exposed to GA for 24 h.
  
  
  
  GA caused epigenetic modulations manifested as histone-3 hypoacetylation (decrease of 25 to 30%, n = 7 to 9) and fragmentation of cAMP-responsive element-binding protein (two-fold increase, n = 6) with 25% decrease in its histone acetyltransferase activity, which resulted in down-regulated transcription of brain-derived neurotrophic factor (0.2- to 0.4-fold, n = 7 to 8) and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (about 0.2-fold, n = 10 to 12). Reversal of histone hypoacetylation with sodium butyrate blocked GA-induced morphological and functional impairments of neuronal development and synaptic communication.
  
  
  
  Long-term impairments of neuronal development and synaptic communication could be caused by GA-induced epigenetic phenomena.
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.|Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Dalla Massara
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Hari Prasad
authors.initials: HP
authors.lastname: Osuru
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Azra
authors.initials: A
authors.lastname: Oklopcic
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.|The Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors.forename: Desanka
authors.initials: D
authors.lastname: Milanovic
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.|Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Srdjan Milan
authors.initials: SM
authors.lastname: Joksimovic
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Caputo
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Michael Robert
authors.initials: MR
authors.lastname: DiGruccio
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ori
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Wang
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.|Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Slobodan Milenko
authors.initials: SM
authors.lastname: Todorovic
authors.affiliation: Departments of Anesthesiology, University of Virginia Health System, Charlottesville, VA, USA.|Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Vesna
authors.initials: V
authors.lastname: Jevtovic-Todorovic
mesh_terms: D000768:Anesthesia, General / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D006657:Histones / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos