title: Regional regulation of glutamate signaling during cuprizone-induced demyelination in the brain.
abstract: Glutamate excitotoxicity is associated with a wide range of neurodegenerative disorders and also seems to be involved in the pathology of demyelinating disorders such as multiple sclerosis (MS). Cuprizone-induced toxic demyelination shows clear characteristics of MS such as demyelination and axonal damage without the involvement of the innate immune system. In this study, we have evaluated glutamate signaling during cuprizone-induced demyelination in the white and gray matter of mouse brain by studying the expression of ionotropic and metabotropic glutamate-receptors and -transporters by Affymetrix gene array analysis, followed by real-time PCR and western blot analysis. Cellular localization of glutamate transporters was investigated by fluorescence double-labeling experiments. Comparing white and gray matter areas, the expression of glutamate receptors was region-specific. Among NMDA receptor subunits, NR2A was up-regulated in the demyelinated corpus callosum (CC), whereas the metabotropic glutamate receptor mGluR2 was down-regulated in demyelinated gray matter. Glutamate-aspartate transporter (GLAST) co-localizing with GFAP(+) astrocytes was increased in both demyelinated CC and telencephalic cortex, whereas Slc1a4 transporter was up-regulated only in CC. Our data indicate that cuprizone treatment affects glutamate-receptors and -transporters differently in gray and white matter brain areas revealing particularly regulation of GLAST and Slc1a4 compared with other genes. This might have an important influence on brain-region selective sensitivity to neurotoxic compounds and the progression of demyelination as has been reported for MS and other demyelinating neurological diseases.
authors.affiliation: Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran; Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany. Electronic address: aazami@kaums.ac.ir.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Azami Tameh
authors.forename: Tim
authors.initials: T
authors.lastname: Clarner
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Atlasi
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Hassanzadeh
authors.forename: Homayoun
authors.initials: H
authors.lastname: Naderian
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000503:physiopathology*; D002478:Cells, Cultured; D002614:Chelating Agents; D003337:Corpus Callosum / Q000378:metabolism; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000503:physiopathology; D040081:Protein Array Analysis; D060888:Real-Time Polymerase Chain Reaction; D017470:Receptors, Glutamate / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D027322:Amino Acid Transport System X-AG; D002614:Chelating Agents; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D003471:Cuprizone
keywords: AMPA; BSA; CC; CNS; Cuprizone; Demyelination; EAAT; EAE; ECL; GFAP; GLAST; GLT; Glutamate receptor; Glutamate transporter; Gria; Grm; HPRT; HRP; IHC; Iba; MAPK; MBP; MGluRs; MOG; MS; N-methyl-d-aspartate; NMDA; NO; PBS; PLP; PVDF; SDS; SLC; TGF-β1; bovine serum albumin; central nervous system; corpus callosum; enhanced chemiluminescence; excitatory amino acid transporter; experimental allergic encephalomyelitis; glial fibrillary acidic protein; glutamate receptor, ionotropic AMPA; glutamate receptor, metabotropic; glutamate transporter; glutamate–aspartate transporter; horseradish peroxidase; hypoxanthine-guanine phosphoribosyltransferase; immunohistochemistry; ionized calcium-binding adaptor molecule; metabotropic glutamate receptors; mitogen-activated protein kinase; multiple sclerosis; myelin basic protein; myelin oligodendrocyte glycoprotein; nitric oxide; phosphate-buffered saline; polyvinylidenfluoride; proteolipid protein; sodium dodecylsulfate; solute carrier; transforming growth factor-beta 1; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid