Increased expression of receptor phosphotyrosine phosphatase-β/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes
| Autor: | Takeshi Sakurai, Patrick R. Hof, Miguel Gama-Sosa, Gregory A. Elder, R J Koch, Lisa Krug, Nathan P. Dorr, Joseph D. Buxbaum, Ozlem Bozdagi-Gunal, Nagahide Takahashi, Ruth H. Walker, J Moy, Kenneth L. Davis |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Mice Transgenic glutamate Biology behavioral disciplines and activities Gene Expression Regulation Enzymologic neuregulin Mice Young Adult GABA 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine mental disorders medicine Animals Humans Receptor Biological Psychiatry ERBB4 030304 developmental biology 0303 health sciences Receptor-Like Protein Tyrosine Phosphatases Class 5 animal model Middle Aged medicine.disease Phenotype Oligodendrocyte Up-Regulation 3. Good health Mice Inbred C57BL schizophrenia Disease Models Animal Psychiatry and Mental health medicine.anatomical_structure Schizophrenia PTPRZ1 Neuregulin Female Original Article dopamine Signal transduction Cognition Disorders Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Translational Psychiatry |
| ISSN: | 2158-3188 |
| Popis: | 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-β/ζ (RPTP β/ζ) and that the gene encoding RPTPβ/ζ (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTPβ/ζ in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTPβ/ζ (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 RPTPβ/ζ 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 RPTPβ/ζ as a therapeutic target in schizophrenia. |
| Databáze: | OpenAIRE |
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