title: Neuronal injury, but not microglia activation, is associated with ketamine-induced experimental schizophrenic model in mice.
abstract: Schizophrenia is a chronic debilitating psychiatric disorder affecting as many as 1% of the population worldwide. Unfortunately, its etiology and pathophysiology are poorly defined. Previous studies have shown that neuronal injury and microglia activation were observed in the schizophrenic patients. The present study aims to evaluate the role of neurons and microglia in ketamine-induced experimental schizophrenic model to further understand its pathophysiology. Firstly, ketamine was used to simulate the behavior abnormalities associated with schizophrenia. The effects of ketamine on mouse locomotor activity, Y-maze task, novel object recognition, and forced swimming test were studied. The results showed that ketamine (25, 50, and 100mg/kg i.p.) administered acutely or repeatedly (for 7 days) can increase the locomotor number significantly. In Y-maze task, ketamine (25, 50, and 100mg/kg) impaired spontaneous alternation after both acute and repeated treatments. In novel object recognition test, acute or chronic ketamine treatment showed no significant effect on mouse exploratory preference behavior. In forced swimming test, repeated treatment of ketamine (100mg/kg) enhanced the immobility duration. Secondly, immunohistochemical method was used to study the changes of neurons and microglia. The results showed that acute treatment of ketamine (100mg/kg) had no effect on neurons in the prefrontal cortex or hippocampus (1, 3, 5, and 7 days after the treatment). In contrast, repeated treatment of ketamine caused neuronal impairment in mouse hippocampus (3rd day, 5th day and 7th day after the final administration). The results of immunohistochemistry demonstrated that microglia in the prefrontal cortex and hippocampus were not affected after acute or repeated administration of ketamine. Finally, the neuronal impairment caused by repeated administration of ketamine was further investigated from the oxidative stress aspects. The results showed that repeated administration of ketamine increased nitric oxide (NO) and nitric oxide synthase (NOS) in prefrontal cortex, hippocampus and serum, while decreased SOD in hippocampus and serum. In summary, chronic ketamine treatment to mice successfully mimics the core behavioral deficits in schizophrenia. It is demonstrated for the first time that neuronal injury was associated with the chronic ketamine-induced experimental schizophrenic model, while microglial cells may play little role in this model. Oxidative stress may contribute to the significant neuronal injury in mouse brain induced by chronic ketamine treatment.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hou
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhang
authors.forename: Guanbo
authors.initials: G
authors.lastname: Xie
authors.forename: Xinyue
authors.initials: X
authors.lastname: Cao
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Mao
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046353:Immobility Response, Tonic / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000097:blood / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000097:blood / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000097:blood / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009569:Nitric Oxide; D008315:Malondialdehyde; D007649:Ketamine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase
keywords: ANOVA; CNS; Ketamine; LSD; MDA; Microglia; N-methyl-d-aspartate; NMDA; NO; NOR; Neurons; Novel object recognition; PCP; SOD; Schizophrenia; TNOS; analysis of variance; central nervous system; least significant difference; malondialdehyde; nitric oxide; phencyclidine; superoxide dismutase; total nitric oxide synthase