4.5 Article

Behavioral and neurobiological changes in a novel mouse model of schizophrenia induced by the combination of cuprizone and MK-801

期刊

BRAIN RESEARCH BULLETIN
卷 174, 期 -, 页码 141-152

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.brainresbull.2021.06.007

关键词

Schizophrenia; Animal model; Cuprizone; MK-801; White matter lesion; Fyn; NMDA receptor

资金

  1. National Natural Science Founda-tion of China [81673406, 81671068, 81473373]
  2. National Science and Technology Major Project for New Drug Research and Development of China [2015ZX0910101601]
  3. Capital Science and Technology Leading Talent Training Project [Z191100006119017]
  4. Beijing Hospitals Authority Ascent Plan [DFL20190803]

向作者/读者索取更多资源

The novel mouse model induced by the combination of CPZ and MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. The mice showed obvious demyelination and white matter damage, along with decreased expression levels of myelin basic protein (MBP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the corpus callosum. Additionally, phosphorylation levels of Fyn and NMDA receptors were noticeably decreased in specific brain regions.
Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N-methyl D-aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Ymaze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2 ',3 '-cyclic nucleotide-3 '-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia.

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