از دست دادن فیبر میلین در کالوزوم مدل موشی اسکیزوفرنی ناشی از MK-801

Previous magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) investigations have shown that the white matter volume and fractional anisotropy (FA) were decreased in schizophrenia (SZ), which indicated impaired white matter integrity in SZ. However, the mechanism underlying these abnormalities has been less studied. The current study was designed to investigate the possible reasons for white matter abnormalities in the mouse model of SZ induced by NMDA receptor antagonist using the unbiased stereological methods and transmission electron microscope technique. We found that the mice treated with MK-801 demonstrated a series of schizophrenia-like behaviors including hyperlocomotor activity and more anxiety. The myelinated fibers in the corpus callosum (CC) of the mice treated with MK-801 were impaired with splitting lamellae of myelin sheaths and segmental demyelination. The CC volume and the total length of the myelinated fibers in the CC of the mice treated with MK-801 were significantly decreased by 9.4% and 16.8% when compared to those of the mice treated with saline. We further found that the loss of the myelinated fibers length was mainly due to the marked loss of the myelinated nerve fibers with the diameter of 0.4–0.5 μm. These results indicated that the splitting myelin sheaths, demyelination and the loss of myelinated fibers with small diameter might provide one of the structural bases for impaired white matter integrity of CC in the mouse model of SZ. These results might also provide a baseline for further studies searching for the treatment of SZ through targeting white matter.

In schizophrenia (SZ) research, a growing body of evidences have provided support for the hypothesis that diminished connectivity referring to abnormal functional integration between different brain regions might be involved in the pathophysiology of SZ, and white matter lesions could be the basis of this disconnectivity (Konrad and Winterer, 2007, Fields, 2008, Stephan et al., 2009 and Schmitt et al., 2011). Earlier structural magnetic resonance imaging (MRI) and postmortem studies have demonstrated smaller white matter volumes in diverse brain regions of SZ, including temporal lobe (Okugawa et al., 2002), caudate nucleus (Takase et al., 2004), anterior limb of the internal capsule (Zhou et al., 2003) and corpus callosum (CC) (Highley et al., 1999 and Chaim et al., 2010). Diffusion tensor imaging (DTI) studies, indicators of the coherence, organization and density of the fibers within the white matter fiber bundles, have also demonstrated impaired white matter integrity in SZ (Kubicki et al., 2007, Lee et al., 2013, Mori et al., 2007 and Skelly et al., 2008). Genetic and postmortem studies have further demonstrated that SZ might be related to myelin sheath abnormalities of myelinated fibers (Hof et al., 2002, Dracheva et al., 2006 and Takahashi et al., 2011). White matter is mainly composed of myelinated nerve fibers. Changes in white matter integrity may be related to alterations in the density of fibers, the coherence of fiber tracts, the number and the diameter of fibers as well as the degree of myelination (Kubicki et al., 2007 and Peters et al., 2010). It is a more direct measure to investigate connectivity of myelinated fibers by postmortem microscopy. However, due to the difficulties in collection of brain samples, to our knowledge, up to now, there have been only a few studies focused on evaluating the fibers in schizophrenics (Casanova et al., 1989, Chance et al., 1999, Highley et al., 1999, Marner and Pakkenberg, 2003 and Uranova et al., 2011). Moreover, those results were inconsistent. For example, Highley et al. (1999) have reported decreased total fiber number and fiber density in the CC in women with SZ, but other investigators have reported that there was no significant difference in the total number of fibers or density of fibers in the CC between schizophrenic patients and controls (Casanova et al., 1989). Such confounders were likely to be influenced by sample selection (sample size, first-episode vs. chronic schizophrenia patients, age, gender) in individual studies (Kuswanto et al., 2012), methodology adopted and neuroimaging techniques used (Marner and Pakkenberg, 2003). In addition, the majority of schizophrenic subjects in these studies have been in illness for long time and have been treated with antipsychotic agent for years, which can influence the results, too (Chen et al., 2013). In fact, the need for models is greater in psychiatry than in other fields (Hyman, 2012), in which the disease tissue is often removed by biopsy or resection and made available for study, however, the brain samples are difficult in collection. In the current study, we assessed the connectivity of white matter with the stereological method and transmission electron microscope technique (Tang et al., 1997 and Tang and Nyengaard, 1997). Firstly, to avoid the confounders such as age, gender, age at onset, duration of illness, antipsychotic medication and so on, we chose the animal model of SZ based on NMDA receptor antagonism. The “NMDA receptor antagonism” theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist to the NMDA subtype of glutamate receptor, induced schizophrenia-like behaviors in humans (Javitt and Zukin, 1991). Many researchers have developed animal models of schizophrenia with NMDA receptor antagonists such as PCP, ketamine, and dizocilpine MK-801 (Jentsch et al., 1997, Jentsch and Roth, 1999, Mouri et al., 2007, Neill et al., 2010 and Guo et al., 2010). To date, the animal model of SZ induced by NMDA receptor antagonists such as MK-801 has been widely applied to investigate the pathogenesis of the schizophrenia (Elhardt et al., 2010, Kocerha et al., 2009, Okamura et al., 2010 and Yu et al., 2011). To our knowledge, however, there have been few studies investigating the abnormalities of white matter in animal model of SZ based on NMDA receptor antagonism (Zhang et al., 2012 and Xiu et al., 2014). Therefore, the aim of the current study was to investigate the white matter deficits in animal model of SZ treated with MK-801. With the stereological methods, the accurate quantitative data of microstructure/ultrastructure of myelinated fibers could be provided and the possible mechanism underlying white matter abnormalities in SZ would be interpretated.