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HDAC1 links early life stress to schizophrenia-like phenotypes.

ABSTRACT: 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.

SUBMITTER: Bahari-Javan S

PROVIDER: S-EPMC5468618 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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HDAC1 links early life stress to schizophrenia-like phenotypes.

Bahari-Javan Sanaz S Varbanov Hristo H Halder Rashi R Benito Eva E Kaurani Lalit L Burkhardt Susanne S Anderson-Schmidt Heike H Anghelescu Ion I Budde Monika M Stilling Roman M RM Costa Joan J Medina Juan J Dietrich Detlef E DE Figge Christian C Folkerts Here H Gade Katrin K Heilbronner Urs U Koller Manfred M Konrad Carsten C Nussbeck Sara Y SY Scherk Harald H Spitzer Carsten C Stierl Sebastian S Stöckel Judith J Thiel Andreas A von Hagen Martin M Zimmermann Jörg J Zitzelsberger Antje A Schulz Sybille S Schmitt Andrea A Delalle Ivana I Falkai Peter P Schulze Thomas G TG Dityatev Alexander A Sananbenesi Farahnaz F Fischer André A

Proceedings of the National Academy of Sciences of the United States of America 20170522 23

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 (<i>Hdac1</i>) expression that is linked to altered DNA methylation. <i>Hdac1</i> overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizo ...[more]

PMID: 28533418

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Project description:BackgroundOur previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear.MethodsWith γ-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice.ResultsThe reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial energy metabolism and antioxidation.ConclusionsThese results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1α downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes.

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HDAC1 links early life stress to schizophrenia-like phenotypes.

Publications

HDAC1 links early life stress to schizophrenia-like phenotypes.

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