title: Elevated GFAP induces astrocyte dysfunction in caudal brain regions: A potential mechanism for hindbrain involved symptoms in type II Alexander disease.
abstract: Alexander Disease (AxD) is a "gliopathy" caused by toxic, dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene. Two distinct types of AxD exist. Type I AxD affected individuals develop cerebral symptoms by 4 years of age and suffer from macrocephaly, seizures, and physical and mental delays. As detection and diagnosis have improved, approximately half of all AxD patients diagnosed have onset >4 years and brainstem/spinal cord involvement. Type II AxD patients experience ataxia, palatal myoclonus, dysphagia, and dysphonia. No study has examined a mechanistic link between the GFAP mutations and caudal symptoms present in type II AxD patients. We demonstrate that two key astrocytic functions, the ability to regulate extracellular glutamate and to take up K(+) via K+ channels, are compromised in hindbrain regions and spinal cord in AxD mice. Spinal cord astrocytes in AxD transgenic mice are depolarized relative to WT littermates, and have a three-fold reduction in Ba(2+) -sensitive Kir4.1 mediated currents and six-fold reduction in glutamate uptake currents. The loss of these two functions is due to significant decreases in Kir4.1 (>70%) and GLT-1 (>60%) protein expression. mRNA expression for KCNJ10 and SLC1A2, the genes that code for Kir4.1 and GLT-1, are significantly reduced by postnatal Day 7. Protein and mRNA reductions for Kir4.1 and GLT-1 are exacerbated in AxD models that demonstrate earlier accumulation of GFAP and increased Rosenthal fiber formation. These findings provide a mechanistic link between the GFAP mutations/overexpression and the symptoms in those affected with Type II AxD.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.|Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Minkel
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.|Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tooba Z
authors.initials: TZ
authors.lastname: Anwer
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.|Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Arps
authors.affiliation: Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.|Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Olsen
mesh_terms: D038261:Alexander Disease / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D026481:Blotting, Far-Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D008564:Membrane Potentials / Q000502:physiology; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012249:Rhombencephalon / Q000473:pathology / Q000503:physiopathology*; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D046509:Tissue Culture Techniques; D000098854:Kcnj10 Channel
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; C493396:Slc1a2 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; D018698:Glutamic Acid; D011188:Potassium
keywords: GLT-1; Kir4.1; gliosis; glutamate homeostasis; potassium buffering