Editors' ChoiceSchizophrenia

Alternative rhythms in schizophrenia

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Science Translational Medicine  21 Aug 2019:
Vol. 11, Issue 506, eaaz0299
DOI: 10.1126/scitranslmed.aaz0299

Abstract

A distinct set of rhythmically expressed genes related to mitochondrial function is identified in the brains of patients with schizophrenia.

Schizophrenia is a psychiatric disease which affects approximately 1% of the population with symptoms including delusions, hallucinations, and trouble with concentration. Current medications greatly improve symptoms, but there is a continued drive for safer and more efficacious treatments. Intriguingly, disturbances in the sleep/wake cycle, sleep architecture, hormonal and body temperature rhythms, and circadian gene expression suggest that the circadian system might also be involved in this condition. The dorsolateral prefrontal cortex (dlPFC) of the brain is considered critical for schizophrenia, and although a number of studies have measured gene expression in this area, the gene changes were modest and inconsistent between studies. Therefore, given the possible link with the circadian system, Seney et al. decided to ask whether disruption in daily rhythms in gene expression from the dlPFC exist in schizophrenia patients.

To accomplish this, the authors used time-of-death to order RNA sequencing data from dlPFC samples from 46 subjects with schizophrenia versus 46 sex- and age-matched controls to detect circadian (24 hour) gene expression patterns. They identified 707 diurnally rhythmic genes in controls and 708 rhythmic genes in subjects with schizophrenia, but remarkably the overlap was only 31 genes. The top pathways for the rhythmic genes in controls were circadian rhythms and inflammation, whereas for schizophrenia subjects the top pathways included oxidative phosphorylation and mitochondrial dysfunction. Many of the genes related to mitochondrial dysfunction were differentially detected in other schizophrenia studies. Remarkably, in the schizophrenia subjects, these mitochondrial genes peaked during the day and were suppressed during the night. However, these differences were only revealed by separating the cohort by time-of-death (those that died during the day versus those that died during the night).

This study identifies that subjects with schizophrenia have a discrete set of rhythmic genes in the dlPFC that is largely separate to the rhythmic genes in controls. Limitations of the study include the small sample size and possible interactions with medications. Although the underlying reasons and consequences for this shift have yet to be identified, overall this study clearly shows that circadian rhythms are an important component in schizophrenia.

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