title: Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity.
abstract: Glutamate-induced excitotoxicity is considered as a major cause of neurodegenerative disease. Excitatory amino acid transporters (EAATs) on glial cells are responsible for the homeostasis of extracellular glutamate in the central nervous system which may contribute to the prevention of excitotoxic neurodegeneration. However, the differential EAAT expression in astrocytes and microglia is not fully understood. In this study, we compared the expression of EAATs in astrocytes and microglia, and we assessed the neuroprotective and neurotoxic function of astrocytes and microglia by a co-culture system. RT-PCR analyses detected that astrocytes expressed each EAAT (EAAT1-5) whereas microglia did not express EAAT4. Western blot analyses demonstrated that astrocytes express a much larger amount of membrane-localized EAATs than microglia. Astrocytes prevented excito-neurotoxicity by the reduction of exogenous glutamate whereas microglia did not. Conversely, activated microglia released an excess of glutamate that induced excitotoxic neuronal death. Astrocytes rescued neurons from microglial glutamate-induced death in a ratio-dependent manner. Inhibition of EAATs abolished glutamate uptake and the neuroprotective effect of astrocytes, but it did not alter any microglial neurotoxic or neuroprotective effects. These results revealed that astrocytic EAATs can counteract microglial glutamate-induced neuronal death whereas microglial EAATs are inconsequential to neurotoxicity and neuroprotection.
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liang
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Doi
authors.forename: Jun
authors.initials: J
authors.lastname: Kawanokuchi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sonobe
authors.forename: Shijie
authors.initials: S
authors.lastname: Jin
authors.forename: Izumi
authors.initials: I
authors.lastname: Yawata
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Satoko
authors.initials: S
authors.lastname: Yasuoka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics / Q000378:metabolism; D050581:Excitatory Amino Acid Transporter 4 / Q000235:genetics / Q000378:metabolism; D050582:Excitatory Amino Acid Transporter 5 / Q000235:genetics / Q000378:metabolism; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050581:Excitatory Amino Acid Transporter 4; D050582:Excitatory Amino Acid Transporter 5; D009498:Neurotoxins; D012333:RNA, Messenger; D018698:Glutamic Acid