Research ReportMyelination deficit in a phencyclidine-induced neurodevelopmental model of schizophrenia
Highlights
► Phencyclidine was administered to postnatal rats in a model of schizophrenia. ► Phencyclidine induced prepulse inhibition deficit and hyperlocomotion in rats. ► Phencyclidine decreased myelin basic protein in the frontal cortex of rats. ► Phencyclidine decreased mature oligodendrocytes in the frontal cortex of rats. ► Myelination may play a role in the pathogenesis of schizophrenia.
Introduction
Schizophrenia is a severe and chronic mental illness, and its etiology and pathogenesis remain poorly understood. Dysfunction of neural networks has been demonstrated by chemical and physiologic imaging in the brains of schizophrenic patients (McClure et al., 1998). Myelin dysfunction produces abnormal connectivity of neural networks. The lipid-rich myelin possesses high electrical resistance and low capacitance, and thus acts as an insulator around axons. Damage to the myelin is accompanied by a decrease in conduction velocity and, when severe, cessation of conduction. Dysregulation of myelination-related genes in chronic schizophrenia has been revealed by genome wide expression analysis (Hakak et al., 2001), and deficits in myelin-associated mRNA and protein expression have been reported in brains of elderly schizophrenic patients (Dracheva et al., 2006). In addition, abnormalities of myelination neuro-imaging and ultrastructural pathology of myelinated fibers and oligodendrocytes have been observed in schizophrenic brains (Flynn et al., 2003, Orlovskaya and Uranova, 1997). Therefore, the pathological process underlying schizophrenia may involve an abnormality of brain myelin affecting white matter (Davis et al., 2003, Finelli, 1985, Hageman et al., 1995).
Oligodendrocytes are the myelin-producing cells in the central nervous system. Oligodendrocyte progenitor cells and myelination appear in the mammalian brain during development (Mehler et al., 1995). Glutamate and glutamate receptors are important in modulating development and differentiation of cells including oligodendrocytes, and a key corticolimbic relay area of myelination in the human brain appears in neurodevelopmental stage (Benes et al., 1994, Benes, 2000). Oligodendrocyte progenitor cells contain functional N-methyl-d-aspartate (NMDA) receptors (Gallo et al., 1994), and NMDA glutamate receptors mediate Ca2+ accumulation in central myelin in response to chemical ischemia in vitro (Micu et al., 2006). Phencyclidine (PCP), an NMDA receptor antagonist, can cause psychoses and negative symptoms, and is used as a pharmacological model of schizophrenia (Javitt, 1987). During the development of rat brain, PCP exposure blocks the functions of NMDA receptors in brain developmental processes, influences embryonic cortical neuronal migration, and induces dysfunction of neuronal connections (Behar et al., 1999). In addition, chronic in utero administration of PCP arrests oligodendrocyte differentiation and severely reduces myelin deposition within the postnatal frontal cortex (Lindahl et al., 2008). Thus, PCP injections on postnatal days may induce myelination dysfunction.
In the present project, we investigated schizophrenia-like behaviors and abnormalities of brain myelination in the rats receiving PCP injections on postnatal days. This is a novel study to approach the myelin dysfunction hypothesis of schizophrenia by using the PCP-induced neurodevelopmental model of schizophrenia. Cerebral myelination and mature oligodendrocytes were evaluated by measuring the expressions of myelin basic protein (MBP) and glutathione S-transferase (GST)-π, respectively. In addition, schizophrenia-like behaviors were measured by locomotion and prepulse inhibition (PPI) tests in rats. The measurement of psychostimulant-induced locomotor hyperactivity is a behavioral assay that is often applied to evaluate mouse behavior related to positive schizophrenia symptomatology (Naert et al., 2011). PPI provides an operational measure of sensory gating of subjects, and disruption of PPI has been well documented in schizophrenia patients (Bolino et al., 1994, Braff et al., 1992, Perry and Braff, 1994).
Section snippets
PCP changes locomotion in rats
To evaluate schizophrenia-like behavior, a locomotor activity test was performed to investigate locomotion in rats on PND30. As shown in Fig. 1, the total number of locomotor activity counts in 60 min was significantly increased in the PCP-injected rats compared with the control rats (P<0.05, t-test).
PCP induces PPI impairment in rats
To also evaluate schizophrenia-like behavior, a PPI test was performed to investigate the sensorimotor gating in rats on PND31. Two-way ANOVA showed that PCP [F(1,34)=13.48, P=0.0008] and prepulse
Discussion
The pathological process underlying schizophrenia may involve an abnormality of brain myelin affecting white matter (Davis et al., 2003, Finelli, 1985, Hageman et al., 1995). The myelin dysfunction hypothesis of schizophrenia was first tested in an animal model in the present study. Our study has shown that prenatal administration of PCP induced both schizophrenia-like behavior and cerebral myelin dysfunction in rats.
PCP can cause psychoses and negative symptoms, and has been used as a
Animals
All procedures with animals were performed in accordance with the guidelines established by the Canadian Council on Animal Care and were approved by the Animal Care Committee of the University of Manitoba. The experimental rats were obtained from timed pregnant Sprague-Dawley rats (Charles River, St Constant, QC, Canada). Female rats were housed three or four per cage, with free access to food and water under controlled laboratory conditions (a 12:12 h light/dark cycle with room temperature 20 °C±1
Acknowledgments
This work was supported by the Manitoba Medical Service Foundation, the Health Science Centre Foundation, Manitoba Health Research Council, and the Canadian Institutes of Health Research.
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These authors contributed equally to this work.