Format

Send to

Choose Destination
Brain Struct Funct. 2018 Sep;223(7):3091-3106. doi: 10.1007/s00429-018-1680-7. Epub 2018 May 9.

Protective potential of dimethyl fumarate in a mouse model of thalamocortical demyelination.

Author information

1
Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-University, Mendelstrasse 7, 48149, Münster, Germany. manuela.cerina@ukmuenster.de.
2
Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-University, Mendelstrasse 7, 48149, Münster, Germany.
3
Institute of Physiology I, Westfälische Wilhelms-University, Robert-Koch-Str. 27a, 48149, Münster, Germany.
4
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
5
Epilepsy Research Center, Westfälische Wilhelms-University, Münster, Germany.
6
Department of Neurology, Essen University Hospital, Essen, Germany.
7
Institute of Physiology I, Westfälische Wilhelms-University, Robert-Koch-Str. 27a, 48149, Münster, Germany. tbudde@uni-muenster.de.

Abstract

Alterations in cortical cellular organization, network functionality, as well as cognitive and locomotor deficits were recently suggested to be pathological hallmarks in multiple sclerosis and corresponding animal models as they might occur following demyelination. To investigate functional changes following demyelination in a well-defined, topographically organized neuronal network, in vitro and in vivo, we focused on the primary auditory cortex (A1) of mice in the cuprizone model of general de- and remyelination. Following myelin loss in this model system, the spatiotemporal propagation of incoming stimuli in A1 was altered and the hierarchical activation of supra- and infragranular cortical layers was lost suggesting a profound effect exerted on neuronal network level. In addition, the response latency in field potential recordings and voltage-sensitive dye imaging was increased following demyelination. These alterations were accompanied by a loss of auditory discrimination abilities in freely behaving animals, a reduction of the nuclear factor-erythroid 2-related factor-2 (Nrf-2) protein in the nucleus in histological staining and persisted during remyelination. To find new strategies to restore demyelination-induced network alteration in addition to the ongoing remyelination, we tested the cytoprotective potential of dimethyl fumarate (DMF). Therapeutic treatment with DMF during remyelination significantly modified spatiotemporal stimulus propagation in the cortex, reduced the cognitive impairment, and prevented the demyelination-induced decrease in nuclear Nrf-2. These results indicate the involvement of anti-oxidative mechanisms in regulating spatiotemporal cortical response pattern following changes in myelination and point to DMF as therapeutic compound for intervention.

KEYWORDS:

Auditory cortex; Demyelination; Multiple sclerosis; Remyelination; Spatiotemporal activity pattern; Thalamocortical system; Voltage-sensitive dye

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center