title: Chronic perinatal hypoxia reduces glutamate-aspartate transporter function in astrocytes through the Janus kinase/signal transducer and activator of transcription pathway.
abstract: The cellular and molecular mechanisms that govern the response of the perinatal brain to injury remain largely unexplored. We investigated the role of white matter astrocytes in a rodent model of diffuse white matter injury produced by exposing neonatal mice to chronic hypoxia-a paradigm that mimics brain injury in premature infants. We demonstrate the absence of reactive gliosis in the immature white matter following chronic hypoxia, as determined by astrocyte proliferation index and glial fibrillary acidic protein levels. Instead, Nestin expression in astrocytes is transiently increased, and the glial-specific glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) are reduced. Finally, we demonstrate that Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling-which is important in both astrocyte development and response to injury-is reduced in the white matter following hypoxia, as well as in primary astrocytes exposed to hypoxia in vitro. Hypoxia and JAK/STAT inhibition reduce glutamate transporter expression in astrocytes, but unlike hypoxia JAK/STAT inhibition downregulates GLAST expression without affecting GLT-1, as demonstrated in vitro by treatment with JAK inhibitor I and in vivo by treatment with the JAK/STAT inhibitor AG490 [(E)-2-cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide]. Our findings (1) demonstrate specific changes in astrocyte function after perinatal hypoxia, which might contribute to the particular pathogenesis of perinatal white matter injury, (2) provide evidence that at least part of these changes result from a disturbance of the JAK/STAT pathway by hypoxia, and (3) identify JAK/STAT signaling as a potential therapeutic target to restore normal GLAST expression and uptake of glutamate after perinatal brain injury.
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Raymond
authors.forename: Peijun
authors.initials: P
authors.lastname: Li
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Mangin
authors.forename: Molly
authors.initials: M
authors.lastname: Huntsman
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
mesh_terms: D000367:Age Factors; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D000860:Hypoxia / Q000473:pathology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014316:Tritium / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D027322:Amino Acid Transport System X-AG; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D014316:Tritium; D049452:Green Fluorescent Proteins; D001224:Aspartic Acid; D053612:Janus Kinases; D001973:Bromodeoxyuridine