Increased expression of receptor phosphotyrosine phosphatase-β/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes

Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-beta/zeta (RPTP beta/zeta) and that the gene encoding RPTP beta/zeta (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTP beta/zeta in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTP beta/zeta (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTP beta/zeta signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTPb/f as a therapeutic target in schizophrenia. Translational Psychiatry (2011) 1, e8; doi:10.1038/tp.2011.8; published online 10 May 2011