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

Background-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-as well as in the secondgeneration offspring never exposed to GA. Thus, we 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. We focus on the effects of GA on histone acetylase (HAT) activity of cAMPresponsive element binding protein (CREB) Binding Protein (CBP) and the histone-3 acetylation status in the promoters of the target genes Brain-derived neurotrophic factor (BDNF) and c-Fos known to regulate the development of neuronal morphology and function.Methods-7 day-old rat pups were exposed to a sedative dose of midazolam followed by combined nitrous oxide and isoflurane anesthesia for 6 hours. Hippocampal neurons and organotypic hippocampal slices were cultured in vitro and exposed to GA for 24 hours.Results-GA caused epigenetic modulations manifested as histone-3 hypoacetylation (decrease of 25-30%, n=7-9) and fragmentation of CBP (2-fold increase, n=6) with 25% decrease of its HAT