Cuprizone demyelination induces a unique inflammatory response in the subventricular zone.

James M. Hillis,Osama Al-Dalahmah,Francis G. Szele,Mayara Vieira Mundim,Julie Davies

doi:10.1186/s12974-016-0651-2

James M. Hillis, Osama Al-Dalahmah + Show 3 more

Open Access

https://doi.org/10.1186/s12974-016-0651-2

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Abstract

BackgroundCuprizone 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.MethodsWe 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.ResultsCuprizone 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0651-2) contains supplementary material, which is available to authorized users.

Highlights

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 number of Gal-3+ cells in the SVZ decreased after cuprizone treatment We previously showed that Gal-3 is selectively expressed in the SVZ and regulates SVZ inflammation after injections of the demyelinating virus Theiler’s murine encephalomyelitis virus (TMEV) [16, 22]
The density of complement of differentiation 45 (CD45)+ cells decreased in the SVZ after cuprizone, the proportion that were ionized calcium-binding adapter molecule 1 (Iba1)+ microglia was increased (Fig. 3d)

Summary

Introduction

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. Cuprizone is a copper-chelator that impacts cell metabolism and leads to demyelination, and if continued, eventual oligodendrocytic and neuronal death. The CC in turn forms the roof of the subventricular zone (SVZ), a neural stem cell niche that generates neurons and glia throughout life [9]. The cuprizone model enables investigation into the SVZ response to demyelination and remyelination in the CC. A recent fate-mapping study demonstrated that SVZ cells contributed to remyelination in the CC after cuprizoneinduced demyelination [10]. These cells produced thicker myelin than oligodendrocytes derived from local

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