Modeling of schizophrenia in mice: implications for white matter abnormalities in the pathophysiology of schizophrenia

Abstract

Cuprizone (CPZ) is a copper‐chelating agent that causes central demyelination and behavioral characteristics in C57BL/6 mice that are reminiscent of human schizophrenia (impaired spatial working memory, social interaction, and auditory prepulse inhibition). Based on behavioral observations, we hypothesized that CPZ induces regionally specific damage to white matter, particularly in the forebrain. We examined the forebrains of C57BL/6 mice given 0.2% CPZ‐containing diet and compared with those of normal fed controls. We assessed: demyelination in white matter tracts of the forebrain; myelin breakdown in the main olfactory bulbs (MOB), cerebral cortices (CTX), caudate/putamen (CP), hippocampi (HP), thalamus (TH), and hypothalamus (HY); and, numbers of oligodendrocytes (OLs) in CTX, CP, TH, and HY. Obvious demyelination was observed in the corpus callosum, external capsule, CP, and dorsal hippocampal commisure whereas other tracts seemed to be unaffected. The neuropil of CTX, HP and MOB showed significant myelin breakdown whereas breakdown was mild in TH and HY. The CTX and CP, but not TH and HY, showed dramatic decrease in OL numbers. The data support a notion that abnormal behaviors of CPZ treated mice result from demyelination in the forebrain and suggest a putative role for oligodendrocyte abnormalities in the pathophysiology of schizophrenia. Supported by SIUSOM.