title: Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats.
abstract: Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague-Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5-bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal ketamine exposure.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Cun-Ming
authors.initials: CM
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Hao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Xu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China. xymzyqwu@126.com.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Wu
mesh_terms: D000778:Anesthetics, Dissociative / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D001973:Bromodeoxyuridine; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D005455:Fluorescent Antibody Technique; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D000778:Anesthetics, Dissociative; D007649:Ketamine; D001973:Bromodeoxyuridine
keywords: Hippocampal dentate gyrus; Ketamine; Morris water maze test; Neonatal; Neurogenesis