Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 23, Pages E4686-E4694Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1613842114
Keywords
schizophrenia; histone-deacetylases; early life stress; personalized medicine; HDAC inhibitor
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Funding
- Deutsche Forschungsgemeinschaft (DFG) Research Group [KFO241/PsyCourse Fi981-4, Fi981 11-1]
- DFG [179/1-1/2013, SA1050/2-1]
- European Research Council (ERC) [648898]
- KFO241/PsyCourse Project [FA 241/16-1]
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Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.
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