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Deficits in adult neurogenesis, contextual fear conditioning, and spatial learning in a Gfap mutant mouse model of Alexander disease.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament of mature astrocytes in the mammalian CNS. Dominant gain of function mutations in GFAP lead to the fatal neurodegenerative disorder, Alexander disease (AxD), which is characterized by cytoplasmic protein aggregates known as Rosenthal fibers along with variable degrees of leukodystrophy and intellectual disability. The mechanisms by which mutant GFAP leads to these pleiotropic effects are unknown. In addition to astrocytes, GFAP is also expressed in other cell types, particularly neural stem cells that form the reservoir supporting adult neurogenesis in the hippocampal dentate gyrus and subventricular zone of the lateral ventricles. Here, we show that mouse models of AxD exhibit significant pathology in GFAP-positive radial glia-like cells in the dentate gyrus, and suffer from deficits in adult neurogenesis. In addition, they display impairments in contextual learning and spatial memory. This is the first demonstration of cognitive phenotypes in a model of primary astrocyte disease.

Pubmed ID: 24259590 RIS Download

Mesh terms: Adult Stem Cells | Alexander Disease | Animals | Cell Differentiation | Disease Models, Animal | Fear | Glial Fibrillary Acidic Protein | Gliosis | Hippocampus | Lateral Ventricles | Learning Disorders | Maze Learning | Mice | Mice, Inbred C57BL | Mice, Transgenic | Mutation | Neurogenesis | Neuroglia | Phenylurea Compounds

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Associated grants

  • Agency: NICHD NIH HHS, Id: P30 HD003352
  • Agency: NINDS NIH HHS, Id: R01 NS060120
  • Agency: NICHD NIH HHS, Id: P30-HD03352
  • Agency: NINDS NIH HHS, Id: P01-NS42803
  • Agency: NINDS NIH HHS, Id: P01 NS042803
  • Agency: NINDS NIH HHS, Id: R01-NS060120

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