HDAC1 links early life stress to schizophrenia-like phenotypes

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-06, Vol.114 (23), p.E4686-E4694
Main Authors: Bahari-Javan, Sanaz, Varbanov, Hristo, Halder, Rashi, Benito, Eva, Kaurani, Lalit, Burkhardt, Susanne, Anderson-Schmidt, Heike, Anghelescu, Ion, Budde, Monika, Stilling, Roman M., Costa, Joan, Medina, Juan, Dietrich, Detlef E., Figge, Christian, Folkerts, Here, Gade, Katrin, Heilbronner, Urs, Koller, Manfred, Konrad, Carsten, Nussbeck, Sara Y., Scherk, Harald, Spitzer, Carsten, Stierl, Sebastian, Stöckel, Judith, Thiel, Andreas, von Hagen, Martin, Zimmermann, Jörg, Zitzelsberger, Antje, Schulz, Sybille, Schmitt, Andrea, Delalle, Ivana, Falkai, Peter, Schulze, Thomas G., Dityatev, Alexander, Sananbenesi, Farahnaz, Fischer, André
Format: Article
Language:English
Subjects:
Biological Sciences
Blood
Deoxyribonucleic acid
DNA
DNA methylation
Environmental risk
Gene expression
Hippocampus
Histone deacetylase
Mental disorders
Mice
Neuropsychology
Patients
PNAS Plus
Prefrontal cortex
Risk analysis
Risk factors
Rodents
Schizophrenia
Stress
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1613842114