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

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Previous studies on demyelinating diseases such as multiple sclerosis have implicated white matter abnormalities as an unexpected contributor to a wide range of psychiatric disorders (Fields, 2008). Recently, white matter abnormalities and demyelination have received increasing interest related to psychiatric disorders in light of findings on changes in the expression of myelin‐related genes (Tkachev et al., 2003; Dracheva et al., 2006; Kerns et al., 2010; Takahashi et al., 2011) and previous imaging‐based findings of impaired white matter integrity in schizophrenia (Kubicki et al., 2005; Mori et al., 2007; Seal et al., 2008; Skelly et al., 2008; Lee et al., 2013). However, the mechanism underlying white matter abnormalities in psychiatric disorders remains unclear. A shortage of an animal model to mimic the neuropathological feature of white matter abnormalities in psychiatric disorders aggravates the difficulty of further investigation.
Cuprizone (CPZ), a copper chelator, causes white matter abnormalities in rodents. C57BL/6 mice exposed to CPZ can be used to study the pathogenesis and pathophysiology of white matter deficiencies in the central nervous system. Additionally, there has been a great body of evidence reporting that mice exposed to CPZ might be a potential animal model to examine the putative roles of white matter abnormalities in psychiatric disorders (Herring and Konradi, 2011; Xu and Li, 2011). Mice exposed to CPZ showed a series of abnormal behaviors mimicking the complex symptoms observed in psychiatric disorders (Makinodan et al., 2009; Xu et al., 2009). More interestingly, many of the behavioral changes induced by CPZ could be reversed with antipsychotic drugs, such as clozapine and quetiapine (Xiao et al., 2008; Xu et al., 2010). These effects of antipsychotics on abnormal behaviors seem to be related to their effects on CPZ‐induced demyelination (Zhang et al., 2008; Wang et al., 2015).
Demyelination in the corpus callosum (CC) and other major white matter tracts in CPZ‐exposed mice has been demonstrated in previous studies (Matsushima and Morell, 2001; Zhang et al., 2008; Gudi et al., 2009; Yang et al., 2009; Steelman et al., 2012). However, until now, there have been no studies demonstrating the detailed abnormalities of demyelination induced by CPZ, especially ultrastructural changes of myelin and axons. Detailed investigation of the myelinated fiber changes would shed light on the white matter pathogenesis puzzle in demyelinating diseases and psychiatric disorders. For this purpose, in the current study, we investigated the ultrastructural changes of the myelinated fibers during demyelination induced by CPZ with the unbiased stereological techniques and transmission electron microscope (TEM) technique. First, 6‐week‐old male C57BL/6 mice were given 0.2% CPZ in their diet for 6 weeks. Then, a series of behaviors, the total CC volume, and the related qualitative characteristics and quantitative parameters of myelinated fibers in the CC were assessed.
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