A mouse model for testing remyelinating therapies

Abstract

Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex. Spontaneous remyelination occurred significantly faster in the cerebral cortex than in white matter and reactive astrocytes were more abundant in white matter lesions. Remyelination of white matter and cerebral cortex was therapeutically enhanced by daily injections of thyroid hormone triiodothronine (T3). In summary, we describe an in vivo demyelination/remyelination paradigm that can be powered to determine efficacy of therapies that enhance white matter and cortical remyelination.

Myelin repair stimulated by CNS-selective thyroid hormone action

“…Three brain regions (cortex, hippocampus, and corpus callosum) were evaluated. Consistent with previous reports (11,12,16,17,31), treatment with T3 resulted in elevated numbers of ASPA-positive oligodendrocytes and increased myelin basic protein (MBP) staining in the hippocampus and cortex relative to that in controls (Figure 2, D-F, and Supplemental Figure 3, A, B, G, and H) but no changes in OPC levels (Supplemental Figure 3, C, D, F, I, J, and L). Treatment with sobetirome increased oligodendrocyte numbers and MBP staining to a lesser extent than treatment with T3 ( Figure 2, E and F).…”

Reversible Loss of Hippocampal Function in a Mouse Model of Demyelination/Remyelination

“…We report large changes in neuronal firing rates, with both fast and long-term components that followed the initiation and cessation of cuprizone diet. These changes were associated with the demyelination and remyelination processes, as were previously reported, and are in agreement with behavioral deficits and recovery that were also reported in cuprizone mice (Sachs et al, 2014;Bai et al, 2016), (Pilz et al, 2016). However, the cuprizone diet reduced the activity even further, and the termination of cuprizone diet was followed by a noticeable recovery.…”

“…This highlights the necessity to understand the impact of these cycles on brain activity. In this study, we measured the effects of cuprizone diet, such as demyelination and remyelination, on hippocampal activity, which recapitulates the loss and partial recovery of myelin, consistently in the same brain regions and with a reliable and reproducible time course (Dutta et al, 2013;Sachs et al, 2014;Bai et al, 2016). We combined electrophysiology and functional microscopy for acute and long-term monitoring of the activity of projection neurons in CA1 and DG regions with cellular resolution over more than 100 days, during both the demyelination and remyelination phases.…”

“…Previous studies have identified that the hippocampus is severely demyelinated following 6-12 weeks of cuprizone diet, and that additional injections of rapamycin have eliminated the spontaneous remyelination that occurs when mice are fed with cuprizone (Sachs et al, 2014;Bai et al, 2016). These mice performed poorly in a hippocampus-dependent spatial-memory task (Dutta et al, 2013).…”

Ultrahigh field imaging of myelin disease models: Toward specific markers of myelin integrity?

“…Typically, early demyelination occurs during the first 3 weeks of intoxication, followed by severe demyelination up to 5 weeks of cuprizone administration. The affected regions predominantly include the corpus callosum and the cerebellar peduncles (Matsushima & Morell, ; Suzuki & Kikkawa, ), but the demyelination process may be more diffuse in the brain, especially when cuprizone intoxication is prolonged up to 10–12 weeks, leading to a gray matter demyelination component, involving in particular cortical areas (Bai et al, ; Skripuletz, Gudi, Hackstette, & Stangel, ). One of the unique features of the cuprizone model is that spontaneous remyelination occurs after withdrawal of the neurotoxin, which makes it well suited to study the dynamics of demyelination and remyelination.…”