GluR2-free alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors intensify demyelination in experimental autoimmune encephalomyelitis.
We adopted a genetic approach to test the importance of edited GluR2-free, Ca(2+)-permeable, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the pathophysiology of experimental autoimmune encephalomyelitis, an inflammatory demyelinative disorder resembling multiple sclerosis. Initial studies showed that oligodendroglial lineage cells from mice lacking functional copies of the gene encoding the GluR3 AMPA receptor subunit (Gria3) had a diminished capacity to assemble edited GluR2-free AMPA receptors, and were resistant to excitotoxicity in vitro. Neurological deficits and spinal cord demyelination elicited by immunization with myelin oligodendrocyte glycoprotein peptide were substantially milder in these Gria3 mutant mice than in their wild-type littermates. These results support the hypothesis that oligodendroglial excitotoxicity mediated by AMPA receptors that do not contain edited GluR2 subunits contributes to demyelination in experimental autoimmune encephalomyelitis, and suggest that inhibiting these Ca(2+)-permeable AMPA receptors would be therapeutic in multiple sclerosis.
Bannerman
Peter
P
UC Davis School of Medicine, Shriners Hospital, Sacramento, California 95817, USA.
Horiuchi
Makoto
M
Feldman
Daniel
D
Hahn
Ashleigh
A
Itoh
Aki
A
See
Jill
J
Jia
Zheng Ping
ZP
Itoh
Takayuki
T
Pleasure
David
D
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D018091:Receptors, AMPA / Q000172:deficiency* / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D018709:Statistics, Nonparametric
D018683:Excitatory Amino Acid Agents; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C104723:glutamate receptor ionotropic, AMPA 3; C067506:1-naphthylacetylspermine; D013096:Spermine; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid