title: Role of histone acetylation in long-term neurobehavioral effects of neonatal Exposure to sevoflurane in rats.
abstract: Human studies, and especially laboratory studies, provide evidence that early life exposure to general anesthesia may affect neurocognitive development via largely unknown mechanisms. We explored whether hippocampal histone acetylation had a role in neurodevelopmental effects of sevoflurane administered to neonatal rats. Male Sprague-Dawley rats were exposed to 3% sevoflurane or were subjected to maternal separation only for 2h daily at postnatal days 6, 7, and 8. The histone deacetylase inhibitor, sodium butyrate (250mg/kg, intraperitoneally), or saline was administered starting 2h prior to anesthesia or maternal separation and continued daily until the end of behavioral tests, which were performed between postnatal days 33 and 50. Upon completion of the behavioral tests, the brain tissues were harvested for further analysis. Rats neonatally exposed to sevoflurane exhibited decreased freezing time in the fear conditioning contextual test and increased escape latency, decreased time in target quadrant, and number of platform crossings in the Morris water maze test. The sevoflurane-exposed rats had lower hippocampal density of dendritic spines, reduced levels of the brain-derived neurotrophic factor, c-fos protein, microtubule-associated protein 2, synapsin1, postsynaptic density protein 95, pCREB/CREB, CREB binding protein, and acetylated histones H3 and H4, and increased levels of histone deacetylases 3 and 8. These neurobehavioral abnormalities were normalized in the sevoflurane-exposed rats treated with sodium butyrate. Our findings provide evidence that neonatal exposure to sevoflurane induces neurobehavioral abnormalities and long-lasting alterations in histone acetylation; normalization of histone acetylation may alleviate the neurodevelopmental side effects of the anesthetic.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Jiao-Jiao
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Ze-Min
authors.initials: ZM
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Ling-Sha
authors.initials: LS
authors.lastname: Ju
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Mu-Huo
authors.initials: MH
authors.lastname: Ji
authors.affiliation: Department of Anesthesiology, University of Florida, Gainesville, Florida, USA.|McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
authors.forename: Anatoly E
authors.initials: AE
authors.lastname: Martynyuk
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.|Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008426:Maternal Deprivation; D008738:Methyl Ethers / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D013995:Time
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D008738:Methyl Ethers; D008869:Microtubule-Associated Proteins; D016760:Proto-Oncogene Proteins c-fos; D000077149:Sevoflurane
keywords: Hippocampus; Histone acetylation; Maternal separation; Neonatal rats; Sevoflurane; Synaptic plasticity