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glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer's disease

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Neural Regeneration Research 2019年第6期14卷 1037-1045页

作者： Ning Li Yang Li Li-Juan Li Ke Zhu Yan Zheng Xiao-Min Wang Department of Neurobiology Capital Medical University Key Laboratory for Neurodegenerative Disorders of the Ministry of Education Capital Medical University Beijing Institute for Brain Disorders Department of Physiology Capital Medical University

Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17, 2

关键词： nerve regeneration Alzheimer’s disease synaptic plasticity hippocampus learning and memory long-term potentiation βamyloid glutamate receptor synaptic strength neural regeneration

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glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells

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Cellular & Molecular Immunology 2021年第10期18卷 2383-2392页

作者： Md Abdul Alim Mirjana Grujic Paul W.Ackerman Per Kristiansson Pernilla Eliasson Magnus Peterson Gunnar Pejler Department of Public Health and Caring Sciences General Medicine and Preventive MedicineUppsala UniversityUppsalaSweden Department of Medical Biochemistry and Microbiology Uppsala UniversityUppsalaSweden Department of Molecular Medicine and Surgery Karolinska InstituteStockholmSweden Department of Orthopedics and Sports Medicine Linköping UniversityLinköpingSweden Academic Primary Health Care UppsalaSweden Department of Anatomy Physiology and BiochemistrySwedish University of Agricultural SciencesUppsalaSweden

Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We previously found that mast cells located within healing tendons can express glutamate receptors,raising the possibility that mast cells may be sensitive to glutamate signaling.To evaluate this hypothesis,we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type(NMDAR1,NMDAR2A,and NMDAR2B)and the metabotropic type(mGluR2 and mGluR7)at both the mRNA and protein levels.The binding of glutamate to glutamate receptors on the mast cell surface was confirmed.Further,glutamate had extensive effects on gene expression in the mast cells,including the upregulation of proinflammatory components such as IL-6 and CCL2.glutamate also induced the upregulation of transcription factors,including Egr2,Egr3 and,in particular,FosB.The extensive induction of FosB was confirmed by immunofluorescence assessment.glutamate receptor antagonists abrogated the responses of the mast cells to glutamate,supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells.Finally,we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons.Together,these findings establish glutamate as an effector of mast cell function,thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

关键词： glutamate glutamate receptors Mast cells NMDA receptors Tryptase

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glutamate reduces experimental intestinal hyperpermeability and facilitates glutamine support of gut integrity

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World Journal of Gastroenterology 2011年第12期17卷 1569-1573页

作者： Mechteld AR Vermeulen Jeffrey de Jong Mathijs J Vaessen Paul AM van Leeuwen Alexander PJ Houdijk Department of Surgery VU University Medical Center1007 MB AmsterdamThe Netherlands Department of Surgery Gemini Hospital1782 GZ Den HelderThe Netherlands Department of Surgery Medical Center Alkmaar1815 JD AlkmaarThe Netherlands

AIM:To assess whether glutamate plays a similar role to glutamine in preserving gut wall integrity.METHODS:The effects of glutamine and glutamate on induced hyperpermeability in intestinal cell lines were studied.Paracellular hyperpermeability was induced in Caco2.BBE and HT-29CL.19A cell lines by adding phorbol-12,13-dibutyrate(PDB) apically,after which the effects of glutamine and glutamate on horseradish peroxidase(HRP) diffusion were studied.An inhibitor of glutamate transport(L-trans-pyrrolidine-2,4-dicarboxylic acid:trans-PDC) and an irreversible blocker(acivicin) of the extracellular glutamine to glutamate converting enzyme,γ-glutamyltransferase,were used.RESULTS:Apical to basolateral HRP flux increased significantly compared to controls not exposed to PDB (n=30,Pglutamate application reduced hyperpermeability by 30%and 20%,respectively.Incubation of HT29CL.19A cells with acivicin and subsequent PDB and glutamine addition increased permeability levels.Incubation of Caco2.BBE cells with trans-PDC followed by PDB and glutamate addition also resulted in high permeability levels.CONCLUSION:Apical glutamate-similar to glutaminecan decrease induced paracellular hyperpermeability.Extracellular conversion of glutamine to glutamate and subsequent uptake of glutamate could be a pivotal step in the mechanism underlying the protective effect of glutamine.

关键词：顶端 Basolateral 流动 glutamate 夫酸安内脏保护内脏墙正直肠渗透

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glutamate in cancers:from metabolism to signaling

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The Journal of Biomedical Research 2020年第4期34卷 260-270页

作者： Haowei Yi Geoff Talmon Jing Wang Department of Genetics Cell Biology and AnatomyUniversity of Nebraska Medical CenterOmahaNE 68198USA. Department of Pathology and Microbiology University of Nebraska Medical CenterOmahaNE 68198USA. Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical CenterOmahaNE 68198USA.

Glutamine and glutamate are major bioenergy substrates for normal and cancer cell growth.Cancer cells need more biofuel than normal tissues for energy supply,anti-oxidation activity and biomass production.Genes related to metabolic chains in many cancers are somehow mutated,which makes cancer cells more glutamate dependent.Meanwhile,glutamate is an excitatory neurotransmitter for conducting signals through binding with different types of receptors in central neuron system.Interestingly,increasing evidences have shown involvement of glutamate signaling,guided through their receptors,in human malignancy.Dysregulation of glutamate transporters,such as excitatory amino acid transporter and cystine/glutamate antiporter system,also generates excessive extracellular glutamate,which in turn,activates glutamate receptors on cancer cells and results in malignant growth.These features make glutamate an attractive target for anti-cancer drug development with some glutamate targeted but blood brain barrier impermeable anti-psychosis drugs under consideration.We discussed the relevant progressions and drawbacks in this field herein.

关键词： glutamate cancers metabolism glutamate receptors glutamate transporters

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glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

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World Journal of Psychiatry 2018年第2期8卷 51-63页

作者： Georgia M Parkin Madhara Udawela Andrew Gibbons Brian Dean Molecular Psychiatry Laboratory the Florey Institute of Neuroscience and Mental Health CRC for Mental Health Research Centre for Mental Health the Faculty of Health Arts and Design Swinburne University

glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the presynaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter(EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.

关键词： Glia Excitatory amino acid transporter Psychiatry Affective disorders glutamate transporter glutamate Schizophrenia

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glutamate Transporter 1-mediated Antidepressant-like Effect in a Rat Model of Chronic Unpredictable Stress

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第6期34卷 838-844页

作者：陈建新姚丽华徐碧波钱坤王惠玲刘忠纯王晓萍王高华 Department of Psychiatry Renmin Hospital Wuhan University Department of Psychology Faculty of Education Hubei University Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

In recent years, more attention has been paid to the role of the glutamate transporter 1 （GLT-1, EAAT2） in major depressive disorder （MDD）. However, experimental data on brain GLT-1 levels are, to some extent, inconsistent in human postmortem and animal studies, These discrepancies imply that the role of GLT-1 in the pathophysiology of MDD and the action of antidepressants remain obscure. This work was designed to study the impact of chronic unpredictable stress （CUS） for 2 ses- sions per day for 35 days and four weeks of fluoxetine （FLX） on depressive-like behaviors in rats, as well as the concomitant expression of the GLT-1 protein in the hippocampus. Behavioral changes were assessed by the sucrose preference and open field tests. GLT-1 levels were detected by immunohisto- chemistry and Western blot analysis. Our study demonstrated that the animals exposed to CUS showed depressive-like behaviors and exhibited a significant decrease in GLT-1 expression in the hippocampus. Chronic FLX treatment reversed the behavioral deficits and the CUS-induced decrease in GLT-1 levels. Taken together, our results support the reduction of GLT-1 in human postmortem studies in MDD and suggest that GLT-1 may be involved in the antidepressant activity of FLX. Our studies further support the notion that GLT-1 is an attractive candidate molecule associated with the fundamental processes of MDD and may be a potential, and novel pharmacological target for the treatment of MDD.

关键词： chronic unpredictable stress glutamate transporter 1 glutamate fluoxetine hippocampus

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Achyranthes bidentata polypeptides prevent apoptosis by inhibiting the glutamate current in cultured hippocampal neurons

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Neural Regeneration Research 2020年第6期15卷 1086-1093页

作者： Rong-Lu Pan Wen-Qing Hu Jie Pan Li Huang Cheng-Cheng Luan Hong-Mei Shen Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Institute of Nautical Medicine Co-Innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina Department of Neurobiology Physiology and BehaviorCollege of Biological ScienceDavisCAUSA Affiliated Mental Health Center of Nantong University Nantong Brain HospitalNantongJiangsu ProvinceChina

glutamate-induced excitotoxicity plays a critical role in the neurological impairment caused by middle cerebral artery occlusion.Achyranthes bidentata polypeptides have been shown to protect against neurological functional damage caused by middle cerebral artery occlusion,but the underlying neuroprotective mechanisms and the relationship to glutamate-induced excitotoxicity remain unclear.Therefore,in the current study,we investigated the protective effects of Achyranthes bidentata polypeptides against glutamate-induced excitotoxicity in cultured hippocampal neurons.Hippocampal neurons were treated with Mg^2+-free extracellular solution containing glutamate(300μM)for 3 hours as a model of glutamate-mediated excitotoxicity(glutamate group).In the normal group,hippocampal neurons were incubated in Mg^2+-free extracellular solution.In the Achyranthes bidentata polypeptide group,hippocampal neurons were incubated in Mg^2+-free extracellular solution containing glutamate(300μM)and Achyranthes bidentata polypeptide at different concentrations.At 24 hours after exposure to the agents,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Hoechst 33258 staining were used to assess neuronal viability and nuclear m'orphology,respectively.Caspase-3 expression and activity were evaluated using western blot assay and colorimetric enzymatic assay,respectively.At various time points after glutamate treatment,reactive oxygen species in cells were detected by H2 DCF-DA,and mitochondrial membrane potential was detected by rhodamine 123 staining.To examine the effect of Achyranthes bidentata polypeptides on glutamate receptors,electrophysiological recording was used to measure the glutamate-induced inward current in cultured hippocampal neurons.Achyranthes bidentata polypeptide decreased the percentage of apoptotic cells and reduced the changes in caspase-3 expression and activity induced by glutamate.In addition,Achyranthes bidentata polypeptide attenuated the amplitude of the glutamate-induced current.Furthermore,t

关键词： Achyranthes bidentata polypeptides apoptosis caspase-3 excitotoxicity glutamate receptors mitochondrial dysfunction mitochondrial membrane potential neuroprotection reactive oxygen species staurosporine

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Osthole improves synaptic plasticity in the hippocampus and cognitive function of Alzheimer's disease rats via regulating glutamate

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Neural Regeneration Research 2012年第30期7卷 2325-2332页

作者： Xiaohua Dong Li Zhang Wei Li Xianyong Meng Department of Pharmacology College of Pharmacy Hebei Medical University Shijiazhuang 050017 Hebei Province China Department of Pharmacology School of Medicine Hebei North University Zhangjiakou 075000 Hebei Province China Department of Orthopedics the First Attached Hospital Hebei North University Zhangjiakou 075000 Hebei Province China

Osthole, an effective monomer in Chinese medicinal herbs, can cross the blood-brain barrier and protect against brain injury, with few toxic effects. In this study, a rat model of Alzheimer＇s disease was established after intracerebroventricular injection of β-amyloid peptide （25-35）. Subsequently the rats were intraperitoneally treated with osthole （12.5 or 25.0 mg/kg） for 14 successive days. Results showed that osthole treatment significantly improved cognitive impairment and protected hippocampal neurons of AIzheimer＇s disease rats. Also, osthole treatment alleviated suppressed long-term potentiation in the hippocampus of Alzheimer＇s disease rats. In these osthole-treated Alzheimer＇s disease rats, the level of glutamate decreased, but there was no significant change in y-amino-butyric acid. These experimental findings suggest that osthole can improve learning and memory impairment, and increase synaptic plasticity in Alzheimer＇s disease rats. These effects of osthole may be because of its regulation of central glutamate and y-amino-butyric acid levels.

关键词： osthole Alzheimer＇s disease learning and memory long-term potentiation glutamate y-amino-butyric acid β-amyloid peptide brain hippocampus neural regeneration

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Neuroprotection by sodium ferulate against glutamate-induced apoptosis is mediated by ERK and PI3 kinase pathways

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Acta Pharmacologica Sinica 2007年第12期28卷 1881-1890页

作者： Ying JIN~(2,4),En-zhi YAN~2,Ying FAN~2,Xiao-li GUO~2,Yan-jie ZHAO~2,Zhi-hong ZONG~3,Zhuo LIU~2~2 Department of Pharmacology,Liaoning Medical University,Jinzhou 121001,China ~3 Department of Biochemistry,China Medical University,Shengyang 110001,China Department of Pharmacology Liaoning Medical University Jinzhou China Department of Biochemistry China Medical University Shengyang China

Aim:To investigate whether sodium ferulate (SF) can protect cortical neuronsfrom glutamate-induced neurotoxicity and the mechanisms responsible for thisprotection.Methods:Cultured cortical neurons were incubated with 50 μmol/Lglutamate for either 30 min or 24 h,with or without pre-incubation with SF (100,200,and 500 μmol/L,respectively).LY294002,wortmannin,PD98059,and U0126were added respectively to the cells 1 h prior to SF treatment.After incubationwith glutamate for 24 h,neuronal apoptosis was quantified by scoring the per-centage of cells with apoptotic nuclear morphology after Hoechst 33258 staining.After incubation with glutamate for either 30 min or 24 h,cellular extracts wereprepared for Western blotting of active caspase-3,poly (ADP-ribose) polymerase(PARP),μ-calpain,Bcl-2,phospho-Akt,phosphorylated ribosomal protein S6 pro-tein kinase (p70S6K),phospho-mitogen-activated protein kinase kinase (MEK1/2)and phosphorylated extracellular signal-regulated kinase (ERK) 1/2.Results:SFreduced glutamate-evoked apoptotic morphology,active caspase-3 proteinexpression,and PARP cleavage and inhibited the glutamate-induced upregulationof the μ-calpain protein level.The inhibition of the phosphatidylinositol 3-kinase(PI3K) and the MEK/ERK1/2 pathways partly abrogated the protective effect ofSF against glutamate-induced neuronal apoptosis.SF prevented the glutamate-induced decrease in the activity of the PI3K/Akt/p70S6K and the MEK/ERK1/2pathways.Moreover,incubation of cortical neurons with SF for 30 min inhibitedthe reduction of the Bcl-2 expression induced by glutamate.Conclusion:Theresults indicate that PI3K/Akt/p70S6K and the MEK/ERK signaling pathwaysplay important roles in the protective effect of SF against glutamate toxicity incortical neurons.

关键词： ferulic acid glutamate extracellular signalregulated kinase phosphatidylinositol 3kinase cortical neurons Bcl-2 μ-calpain

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A preliminary experimental study on the cardiac toxicity of glutamate and the role of α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptor in rats

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Chinese Medical Journal 2013年第7期126卷 1323-1332页

作者： LIU Yan ZHOU Lan XU Hai-fei YAN Li DING Fan HAO Wei CAO Ji-min GAO Xue Department of Physiology and Pathophysiology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College Beijing 100005 China

Background Monosodium L-glutamate （MSG） is a food flavour enhancer and its potential harmfulness to the heart remains controversial. We investigated whether MSG could induce cardiac arrhythmias and apoptosis via the （α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid （AMPA） receptor. Methods Myocardial infarction （MI） was created by ligating the coronary artery and ventricular arrhythmias were monitored by electrocardiogram in the rat in vivo. Neonatal rat cardiomyocytes were isolated and cultured. Cell viability was estimated by 3-（4,5）-dimethylthiahiazo（-z-yl）-3,5-di-phenytetrazoliumromide （MTT） assay. Calcium mobilization was monitored by confocal microscopy. Cardiomyocyte apoptosis was evaluated by acridine orange staining, flow cytometry, DNA laddering, reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting. Results MSG （i.v.） decreased the heart rate at 0.5 g/kg and serious bradycardia at 1.5 g/kg, but could not induce ventricular tachyarrhythmias in normal rats in vivo. In rats with acute MI in vivo, however, MSG （1.5 g/kg, i.v.） induced ventricular tachyarrhythmias and these arrhythmias could be prevented by blocking the AMPA and N-methyl-d-aspartate （NMDA） receptors. Selectively activating the AMPA or NMDA receptor induced ventricular tachyarrhythmias in MI rats. At the cellular level, AMPA induced calcium mobilization, oxidative stress, mitochonddal dysfunction and apoptosis in cultured cardiomyocytes, especially when the AMPA receptor desensitization were blocked by cyclothiazide. The above toxic cellular effects of AMPA were abolished by AMPA receptor blockade or by H202 scavengers. Conclusions MSG induces bradycardia in normal rats, but triggers lethal tachyarrhythmias in myocardial infarcted rats probably by hindering AMPA receptors. AMPA receptor overstimulation also induces cardiomyocyte apoptosis, which may facilitate arrhythmia.

关键词： glutamate AMPA receptor apoptosis arrhythmia myocardial infarction

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