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Brain Advance Access published online on September 22, 2007
Brain, doi:10.1093/brain/awm219
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing–remitting experimental autoimmune encephalomyelitis

Stine Rasmussen1,3, Yue Wang1, Pia Kivisäkk1, Roderick T. Bronson2, Morten Meyer3, Jaime Imitola1,* and Samia J. Khoury1,*

1Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, 2Department of Pathology, Harvard Medical School, Boston, MA 02115, USA and 3Department of Anatomy and Neurobiology, University of Southern Denmark, DK-5000 Odense C, Denmark

Correspondence to: Jaime Imitola, MD or Samia J. Khoury, MD, 77 Avenue Louis Pasteur R710, Harvard Institutes of Medicine, Boston, MA 02115, USA E-mail: jimitola{at}rics.bwh.harvard.edu or skhoury{at}rics.bwh.harvard.edu

Cortical pathology, callosal atrophy and axonal loss are substrates of progression in multiple sclerosis (MS). Here we describe cortical, periventricular subcortical lesions and callosal demyelination in relapsing–remitting experimental autoimmune encephalomyelitis in SJL mice that are similar to lesions found in MS. Unlike the T-cell infiltrates that peak during acute disease, we found that microglia activation persists through the chronic disease phase. Microglia activation correlated with abnormal phosphorylation of neurofilaments in the cortex and stripping of synaptic proteins in cortical callosal projecting neurons. There was significant impairment of retrograde labeling of NeuN-positive callosal projecting neurons and reduction in the labelling of their transcallosal axons. These data demonstrate a novel paradigm of cortical and callosal neuropathology in a mouse model of MS, perpetuated by innate immunity. These features closely mimic the periventricular and cortical pathology described in MS patients and establish a model that could be useful to study mechanisms of progression in MS.

Key Words: EAE; callosal projecting neurons; microglia; MS; neurodegeneration; live imaging

Abbreviations: MS, multiple sclerosis; NAWM, normal-appearing white matter

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Received May 17, 2007. Revised July 20, 2007. Accepted August 21, 2007.

*These authors contributed equally to this work as co-senior authors.


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