title: Cuprizone demyelination induces a unique inflammatory response in the subventricular zone.
abstract: Cuprizone leads to demyelination of the corpus callosum (CC) and activates progenitor cells in the adjacent subventricular zone (SVZ), a stem cell niche which contributes to remyelination. The healthy SVZ contains semi-activated microglia and constitutively expresses the pro-inflammatory molecule galectin-3 (Gal-3) suggesting the niche uniquely regulates inflammation.
  
  
  
  We studied the inflammatory response to cuprizone in the SVZ and CC in Gal-3 knockout mice using immunohistochemistry and with the in vitro neurosphere assay.
  
  
  
  Cuprizone caused loss of myelin basic protein (MBP) immunofluorescence in the CC suggesting demyelination. Cuprizone increased the density of CD45+/Iba1+ microglial cells and also increased Gal-3 expression in the CC. Surprisingly, the number of Gal-3+ and CD45+ cells decreased in the SVZ after cuprizone, suggesting inflammation was selectively reduced therein. Inflammation can regulate SVZ proliferation and indeed the number of phosphohistone H3+ (PHi3+) cells decreased in the SVZ but increased in the CC in both genotypes after cuprizone treatment. BrdU+ SVZ cell numbers also decreased in the SVZ after cuprizone, and this effect was significantly greater at 3 weeks in Gal-3 (-/-) mice compared to WT, suggesting Gal-3 normally limits SVZ cell emigration following cuprizone treatment.
  
  
  
  This study reveals a uniquely regulated inflammatory response in the SVZ and shows that Gal-3 participates in remyelination in the cuprizone model. This contrasts with more severe models of demyelination which induce SVZ inflammation and suggests the extent of demyelination affects the SVZ neurogenic response.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Hillis
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.|Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, 04039-032, Brazil.
authors.forename: Mayara Vieira
authors.initials: MV
authors.lastname: Mundim
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.
authors.forename: Osama
authors.initials: O
authors.lastname: Al-Dalahmah
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. Francis.Szele@dpag.ox.ac.uk.
authors.forename: Francis G
authors.initials: FG
authors.lastname: Szele
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003337:Corpus Callosum / Q000187:drug effects / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000209:etiology*; D020547:Lateral Ventricles / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D009830:Olfactory Bulb / Q000187:drug effects / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D037502:Galectin 3; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D008996:Monoamine Oxidase Inhibitors; D003471:Cuprizone
keywords: Corpus callosum; Demyelination; Galectin-3; Inflammation; Multiple sclerosis; Subventricular zone