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Cuprizone Treatment Induces Distinct Demyelination, Astrocytosis, and Microglia Cell Invasion or Proliferation in the Mouse Cerebellum

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Abstract

Demyelination of the cerebellum is a well-known phenomenon in human multiple sclerosis (MS). Concordantly, patients with MS frequently developed symptoms deriving from cerebellar lesions, i.e., dysmetria leading to hand dexterity impairment. Important advances in MS research have been made as a direct or indirect consequence of the establishment of adequate animal models. In this study, we used the cuprizone mouse model to investigate cerebellar demyelination in young adult male mice. The myelin status was analyzed by immunohistochemistry for proteolipoprotein and electron microscopy. The expression and presence of oligodendrocyte, astroglial, and microglia markers were supplementary studied. Cuprizone intoxication induced an almost complete demyelination of cerebellar nuclei. Cerebellar cortex regions were not (cortical gray matter) or only marginally (cortical white matter) affected. In addition, the affected areas displayed hypertrophic and hyperplastic astrocytosis accompanied by microglia or macrophage invasion. We conclude that cuprizone-induced demyelination pictures cerebellar deep gray matter involvement but not cerebellar cortex pathology as described for human MS. Behavioral changes after cuprizone described for this animal model may not only result from effects on commissural fiber tracts but also can arise from cerebellar demyelination.

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Abbreviations

APC:

adenomatous polyposis coli protein

CCx:

cerebellar cortex

CM:

cerebellar marrow

CNS:

central nervous system

cuprizone:

bis-cyclohexanone oxaldihydrazone

EAE:

experimental autoimmune encephalomyelitis

GFAP:

glial fibrillary acidic protein

GL:

granular layer

HPRT:

hypoxanthine-guanine phosphoribosyltransferase

Iba-1:

ionized calcium binding adaptor molecule

IHC:

immunohistochemistry

IN:

interpositus nucleus

LCN:

lateral cerebellar nucleus

MBP:

myelin basic protein

MCN:

medial cerebellar nucleus

ML:

molecular layer

MRI:

magnet resonance imaging

MS:

multiple sclerosis

PL:

pyramidal layer

PLP:

proteolipoprotein

rt:

reverse transcription

RT:

real time

WM:

white matter

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Acknowledgment

We would like to thank U. Zahn, A. Weth and H. Helten for excellence technical assistance. This research project was supported by the START-Program (MK) of the Faculty of Medicine, RWTH Aachen University and seed funds of the RWTH Aachen University (WB).

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Authors and Affiliations

  1. Faculty of Medicine, Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Angela Groebe, Tim Clarner, Jon Dang, Cordian Beyer & Markus Kipp

  2. Department of Cellular Neurobionics, Institute of Zoology, RWTH Aachen University, Kopernikusstraße 16, 52056, Aachen, Germany

    Werner Baumgartner

Authors
  1. Angela Groebe
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  2. Tim Clarner
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  3. Werner Baumgartner
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  4. Jon Dang
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  5. Cordian Beyer
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  6. Markus Kipp
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Correspondence to Markus Kipp.

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Angela Groebe and Tim Clarner contributed equally to this work.

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Groebe, A., Clarner, T., Baumgartner, W. et al. Cuprizone Treatment Induces Distinct Demyelination, Astrocytosis, and Microglia Cell Invasion or Proliferation in the Mouse Cerebellum. Cerebellum 8, 163–174 (2009). https://doi.org/10.1007/s12311-009-0099-3

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