Progress in Neuro-Psychopharmacology and Biological Psychiatry
Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice
Introduction
Xiao et al. (2008) reported that demyelination in the brains of mice which had been administered a copper chelator, cuprizone, led to abnormal behaviors such as spatial working memory impairment and hyperlocomotion (Xiao et al., 2008). Because the former is regarded as an endophenotype of schizophrenia, they proposed that cuprizone-fed mice may represent an animal model of schizophrenia. This study and their following study (Zhang et al., 2008) also revealed that quetiapine ameliorated both the demyelination and the abnormal behaviors, underscoring the causal relationship of the demyelination with schizophrenic symptoms. In addition, high anxiety by cuprizone was also shown in another report (Torkildsen et al., 2009). Therefore, demyelination by cuprizone could be involved in some psychiatric symptoms of mice.
In general, the prognosis of schizophrenia is related to the age at which a patient first develops symptoms: the earlier the onset of schizophrenia, the more severe and prolonged the disturbance due to negative symptoms is likely to be (Alptekin et al., 2005). Several lines of evidence have implicated abnormal myelin and broken white matter in schizophrenia (Hof et al., 2002, Tkachev et al., 2003, Byne et al., 2006) and negative symptoms and cognitive impairment of schizophrenia are thought to be associated with white matter abnormalities (Hof et al., 2003, Wexler et al., 2009). Taking altogether, we hypothesized that the timing of demyelination may influence severity of abnormal behaviors in animal models. To test the hypothesis, we took advantage of the above-mentioned cuprizone-fed mice, because we can easily change the timing of demyelination by altering cuprizone-feeding periods. We produced demyelination by administering cuprizone to mice for 4 weeks, in either the juvenile (early-onset) period or the adult (late-onset) period, and analyzed their behavior just after the cuprizone feeding ended and at the later period when remyelination took place. We found that spatial working memory and social activities were persistently affected in the early-onset demyelination group even at the later period, while late-onset demyelination group showed significant recovery in those functions, suggesting that the timing of demyelination has strong influence on the outcomes of psychosocial behavioral abnormalities.
Section snippets
Animals and treatments
Five female C57BL/6 mice per cage were housed in a temperature- and humidity-controlled animal facility under a reversed light–dark cycle (lights on 8:00–20:00). Mice from different litters were assigned to three groups: control, early demyelination (ED) and late demyelination (LD) groups. Mice in the control group were fed with normal chow throughout, while mice in the ED group were fed with chow containing 0.2% (W/W) cuprizone from postnatal day (P) 29–P56, and those in the LD group were fed
Cuprizone intake produces demyelination and its cessation induces remyelination
The corpus callosum is a representative white matter in mice and humans which could be involved in the pathophysiology of schizophrenia (Gasparotti et al., 2009) and the prefrontal cortex is a responsible region for spatial working memory and social behaviors which are pivotal behaviors for schizophrenia (Brunet-Brunet-Gouet and Decety, 2006, Enomono and Floresco, 2009). We therefore focused on the extent of demyelination and remyelination in these regions after the cessation of cuprizone
Discussion
Increasing data have shown that schizophrenia is a neurodevelopmental disorder which is attributed to genetic and environmental factors (Weinberger, 1987, Weinberger, 1995, Murray et al., 1992, Pearce, 2001, Meyer et al., 2005). Imaging studies revealed not only atrophic gray matter, but also white matter deficits in frontal and temporal lobe (Janssen et al., 2008, Lui et al., 2009, Schneiderman et al., 2009) and postmortem histological examination has shown dysmyelination or oligodendrocytic
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