In prior studies funded by this grant, we established that the oligodendroglial lineage is vulnerable to non-N-methyl-D-aspartate glutamate receptor (non-NMDA-GluR)-mediated excitotoxic necrosis. Meanwhile, others reported that inhibitors of ionotropic GluR diminish severity of experimental autoimmune encephalomyelitis (EAE). During the new granting period, we will determine the properties and composition of the ionotropic GluR that mediate oligodendroglial excitotoxicity, and the role of excitotoxicity in killing oligodendroglia and neurons in mice with EAE elicited by immunization with myelin oligodendrocyte glycoprotein (MOG). A novel and powerful aspect of our studies is the use of mouse strains in which oligodendroglia and neurons have been genetically modified to enhance their in situ visibility, or to alter the permeability properties of their non-NMDA-GluR. These include transgenic mice that express enhanced green fluorescence protein (EGFP) in the oligodendroglial lineage, driven by 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNPase) promoters; transgenic mice that express yellow fluorescence protein (YFP) in motor neurons, driven by the thy1 promoter; and mice lacking functional copies of the gene encoding non-NMDA-GluR GluR2 subunits. Our results will illuminate mechanisms of injury to target oligodendroglia and neurons in EAE, and should prove helpful in determining whether ionotropic GluR inhibitor treatment trials are justified in patients with multiple sclerosis.
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