Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Abstract

Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

Ultrastructural abnormalities and loss of myelinated fibers in the corpus callosum of demyelinated mice induced by cuprizone

“…Behavioral deficits follow the course of demyelination–remyelination induced by administration of CPZ, and the relationship between these deficits and psychiatric disorders has been investigated previously (Franco‐Pons et al, ; Xu et al, ; Herring and Konradi, ; Acharjee et al, ; Wang et al, ). For example, Xu et al () found that mice exposed to CPZ had fewer social interactions and impaired spatial working memory compared with control mice, which was also reported in an independent study by Makinodan et al ().…”

Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

“…As seen in humans, certain behavioral changes can be observed in EAE mice (Acharjee et al, 2013; Franco-Pons et al, 2007; Jones et al, 2008; Legroux and Arbour, 2015; Moore et al, 2014; Serra-de-Oliveira et al, 2015; Ulrich et al, 2010; Wang et al, 2013). Clinical signs and paralysis in EAE mice are scored on a scale from 0 (clinically normal) to 5 (moribund) (Miller et al, 2010).…”

Commentary: Mycoplasma pneumoniae-associated mild encephalitis/encephalopathy with a reversible splenial lesion: Report of two pediatric cases and a comprehensive literature review

“…Premature oligodendrocytes contained less antioxidants and anti-apoptotic Bcl-2 but higher apoptotic Bax than matured cells, being more susceptible to environmental stress including oxidant stress [18][19][20] . In response to demyelinating stimulus, demyelination was more severe in the CC of juvenile and young-adult mice than in middle-aged mice 21 . Sirtuin 3 (Sirt3), which reduces ROS by deacetylating forkhead box O3a that transactivates antioxidant genes, was localized in the ameboid microglial cells and distributed in the CC of the early postnatal rats, and diminished in the ramified microglial cells of the CC in the adult rats 22 .…”