期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 71, 期 6, 页码 1205-1220出版社
SPRINGERNATURE
DOI: 10.1007/s12031-020-01747-w
关键词
Alzheimer's disease; Dentate gyrus; Excitotoxicity; Glutamate; Memantine; NMDAR
资金
- International Society for Neurochemistry ISN-CAEN (Category 1B) research grant
- ISN-CAEN (Category 1A)
The study investigated the acute effects of glutamate injection on behavior and molecular expression in the dentate gyrus, showing that glutamate induced anxiogenic responses and spatial memory impairments, which were inhibited by the NMDAR antagonist memantine.
The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-beta (A beta) accumulation and increased glutamate agonist. While previous studies have shown A beta-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamate-mediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据