Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation

Sarah E. Lutz, Yongmei Zhao, Maria Gulinello, Sunhee C. Lee, Cedric S. Raine, Celia F. Brosnan

Research output: Contribution to journalArticle

139 Scopus citations

Abstract

Astrocytes are coupled via gap junctions (GJs) comprising connexin 43 (Cx43) (Gja1) and Cx30 (Gjb6), which facilitate intercellular exchange of ions. Astrocyte connexins also form heterotypic GJs with oligodendrocytic somata and lamellae. Loss of oligodendrocyte gap junctions results in oligodendrocyte and myelin pathology. However, whether loss of astrocyte GJs affects oligodendrocytes and myelin is not known. To address this question, mice with astrocyte-targeted deletion of Cx43 and global loss of Cx30 [double knock-out (dKO)] were studied using Western blotting, immunohistochemistry, electron microscopy, and functional assays. Commencing around postnatal day 23 and persisting into old age, we found widespread pathology of white matter tracts comprising vacuolated oligodendrocytes and intramyelinic edema. In contrast, gray matter pathology was restricted to theCA1region of the hippocampus, and consisted of edematous astrocytes. No differences were observed in synaptic density or total NeuN+ cells in the hippocampus, or olig2+ cells in the corpus callosum. However, in dKO mice, fewer CC1-positive mature oligodendrocytes were detected, and Western blotting indicated reduced myelin basic protein. Pathology was not noted in mice expressing a single allele of either Cx43 or Cx30. When compared with single connexin knock-outs, dKO mice were impaired in sensorimotor (rotarod, balance beam assays) and spatial memory tasks (object recognition assays). We conclude that loss of astrocytic GJs can result in white matter pathology that has functional consequences.

Original languageEnglish (US)
Pages (from-to)7743-7752
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number24
DOIs
StatePublished - Jun 17 2009

ASJC Scopus subject areas

  • Neuroscience(all)

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