A chemical link between early life stress and adult schizophrenia

A massive collaboration finds that schizophrenia-like symptoms induced by early life stress in mice correlates with expression of a DNA altering enzyme. Inhibition of that enzyme (whose levels are also increased in human patients with early life stress) reduces schizophrenia-like symptoms:

Significance

Early life stress (ELS) is an important risk factor for schizophrenia. Our study shows that ELS in mice increases the levels of histone-deacetylase (HDAC) 1 in brain and blood. Although altered Hdac1 expression in response to ELS is widespread, increased Hdac1 levels in the prefrontal cortex are responsible for the development of schizophrenia-like phenotypes. In turn, administration of an HDAC inhibitor ameliorates ELS-induced schizophrenia-like phenotypes. We also show that Hdac1 levels are increased in the brains of patients with schizophrenia and in blood from patients who suffered from ELS, suggesting that the analysis of Hdac1 expression in blood could be used for patient stratification and individualized therapy.

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.