Multiple sclerosis: Altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage

Glutamate excitotoxicity, recently demonstrated in an animal model of multi ple sclerosis (MS), is evoked by altered glutamate homeostasis. In the pres ent study, we investigated the major regulating factors in glutamate excito toxicity by immunohistochemistry in MS and control white matter with marker s for glutamate production (glutaminase), glutamate transport (GLAST, GLT-1 and EAAT-1), glutamate metabolism (glutamate dehydrogenase [GDH] and gluta mine synthetase [GS]), axonal damage (SMI 32) and CNS cell types. Active MS lesions showed high-level glutaminase expression in macrophages and microg lia in close proximity to dystrophic axons. Correlation between glutaminase expression and axonal damage was confirmed experimentally in animals. Whit e matter from other inflammatory neurologic diseases displayed glutaminase reactivity, whereas normals and noninflammatory conditions showed none. All three glutamate transporters were expressed robustly, mainly on oligodendr ocytes, in normal, control and MS white matter, except for GLT-1, which sho wed low-level expression around active MS lesions. GS and GDH were present in oligodendrocytes in normal and non-MS white matter but were absent from both active and chronic silent MS lesions, suggesting lasting metabolic imp ediments. Thus, imbalanced glutamate homeostasis contributes to axonal and oligodendroglial pathology in MS. Manipulation of this imbalance may have t herapeutic import.