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Alteration of glial‐neuronal metabolic interactions in a mouse model of Alexander disease
Author(s) -
Meisingset Tore Wergeland,
Risa Øystein,
Brenner Michael,
Messing Albee,
Sonnewald Ursula
Publication year - 2010
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.21003
Subject(s) - glutamine , biology , glial fibrillary acidic protein , astrocyte , glutamate receptor , taurine , metabolism , cerebellum , neuroglia , neurotransmitter , genetically modified mouse , medicine , endocrinology , glutamine synthetase , biochemistry , central nervous system , transgene , amino acid , receptor , gene , immunology , immunohistochemistry
Abstract Alexander disease is a rare and usually fatal neurological disorder characterized by the abundant presence of protein aggregates in astrocytes. Most cases result from dominant missense de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP), but how these mutations lead to aggregate formation and compromise function is not known. A transgenic mouse line (Tg73.7) over‐expressing human GFAP produces astrocytic aggregates indistinguishable from those seen in the human disease, making them a model of this disorder. To investigate possible metabolic changes associated with Alexander disease Tg73.7 mice and controls were injected simultaneously with [1‐ 13 C]glucose to analyze neuronal metabolism and [1,2‐ 13 C]acetate to monitor astrocytic metabolism. Brain extracts were analyzed by 1 H magnetic resonance spectroscopy (MRS) to quantify amounts of several key metabolites, and by 13 C MRS to analyze amino acid neurotransmitter metabolism. In the cerebral cortex, reduced utilization of [1,2‐ 13 C]acetate was observed for synthesis of glutamine, glutamate, and GABA, and the concentration of the marker for neuronal mitochondrial metabolism, N‐acetylaspartate (NAA) was decreased. This indicates impaired astrocytic and neuronal metabolism and decreased transfer of glutamine from astrocytes to neurons compared with control mice. In the cerebellum, glutamine and GABA content and labeling from [1‐ 13 C]glucose were increased. Evidence for brain edema was found in the increased amount of water and of the osmoregulators myo ‐inositol and taurine. It can be concluded that astrocyte—neuronal interactions were altered differently in distinct regions. © 2010 Wiley‐Liss, Inc.