White matter abnormalities and animal models examining a putative role of altered white matter in schizophrenia

Abstract

Schizophrenia is a severe mental disorder affecting about 1% of the population worldwide. Although the dopamine (DA) hypothesis is still keeping a dominant position in schizophrenia research, new advances have been emerging in recent years, which suggest the implication of white matter abnormalities in schizophrenia. In this paper, we will briefly review some of recent human studies showing white matter abnormalities in schizophrenic brains and altered oligodendrocyte-(OL-) and myelin-related genes in patients with schizophrenia and will consider abnormal behaviors reported in patients with white matter diseases. Following these, we will selectively introduce some animal models examining a putative role of white matter abnormalities in schizophrenia. The emphasis will be put on the cuprizone (CPZ) model. CPZ-fed mice show demyelination and OLs loss, display schizophrenia-related behaviors, and have higher DA levels in the prefrontal cortex. These features suggest that the CPZ model is a novel animal model of schizophrenia.

Figure 1

Effects of antipsychotics on the CPZ-induced deficits in PPI test. Control and experimentally treated C57BL/6 mice were subjected to PPI test on the same day (14th day after CPZ exposure). (a) The data of the HAL experiment. (b) The data of the CLZ experiment. (c) The data of the QUE experiment. Data were expressed as M ± SEM (n = 6 to 12/group). CNT: control group; CPZ: cuprizone group; CLZ: clozapine group; HAL: haloperidol group; QUE: quetiapine group; CPZ+CLZ: mice received both cuprizone and clozapine; CPZ+HAL: mice received both cuprizone and haloperidol; CPZ+QUE: mice received both cuprizone and quetiapine. PPI: prepulse inhibition; db: decibel. *P < 0.05, **P < 0.01, compared to the CNT group; ⁺ P < 0.05, compared to the CPZ group.

Figure 2

Effects of antipsychotics on the CPZ-induced abnormal performance in the Y-maze test. Control and experimentally treated C57BL/6 mice were subjected to Y-maze test on the same days (21st and 42nd days after CPZ exposure). (a) The data of the spontaneous alternation in the HAL experiment. (b) The data of the number of arm entries in the HAL experiment. (c) The data of the spontaneous alternation in the CLZ experiment. (d) The data of the number of arm entries in the CLZ experiment. (e) The data of the spontaneous alternation in the QUE experiment. (f) The data of the number of arm entries in the QUE experiment. Data were expressed as M ± SEM (n = 6 to 12/group). *P < 0.05, **P < 0.01, compared to the CNT group; ⁺⁺ P < 0.01, compared to the CPZ group.

Figure 3

Effects of antipsychotics on the CPZ-induced deficits in the social interaction. Control and experimentally treated C57BL/6 mice were subjected to social interaction test on the same day (28th day after CPZexposure). (a) The data of the HAL experiment. (b) The data of the CLZ experiment. (c) The data of the QUE experiment. Data were expressed as M ± SEM (n = 6 pairs/group). *P < 0.05, **P < 0.01, compared to the CNT group; ⁺ P < 0.05, compared to the CPZ group.

Figure 4

Effects of antipsychotics on the CPZ-induced decrease in MBP in CP. Control and experimentally treated C57BL/6 mice were sacrificed on 43rd day after CPZ exposure. The CP was dissected out of the brain and processed for Western-blot analysis to measure MBP levels. The upper photographs (a), (b), and (c) are representative of Western blots from the HAL, CLZ, and QUE experiments, respectively. The bar charts (d), (e), and (f) in the bottom panel are the statistical results of the amount of MBP relative to β-actin in the same corresponding lanes as labeled. Data were expressed as M ± SEM (n = 6/group). **P < 0.01, compared to the CNT group; ⁺⁺ P < 0.01, compared to the CPZ group.