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

Journal article

Background
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.

Methods
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.

Results
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.

Conclusions
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: Hillis, J; Davies, J; Mundim, M; Al-Dalahmah, O; Szele, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Journal of Neuroinflammation
• Volume: 13
• Article number: 190
• Publication date: 2016-08-22
• Acceptance date: 2016-07-04
• DOI: 10.1186/s12974-016-0651-2
• ISSN: 1742-2094
• Pmid: 27550173
• Language: English
• Keywords: cuprizone; demyelinating diseases; mice, transgenic; glial fibrillary acidic protein; female; gene expression regulation; corpus callosum; olfactory bulb; animals, newborn; monoamine oxidase inhibitors; galectin 3; lateral ventricles; oligodendroglia; disease models, animal; cell proliferation; microfilament proteins; calcium-binding proteins; animals; inflammation; male; mice