Author(s): Olivia Diem 1 , 2 , Marisa Schäffner 1 , Wolfgang Seifarth 2 , Christine Leib-Mösch 1 , 2 , *
Schizophrenia is a highly complex and severe neuropsychiatric disorder with uncertain etiology. Based on data sets from family, twin, and adoption studies, as well as from epidemiological surveys, the etiopathogenesis of schizophrenia involves the interplay of polygenic influences and environmental risk factors operating on brain maturation during pregnancy , , , . Susceptibility to environmental factors may be under genetic control and, vice versa, environmental factors can influence the genomic imprint leading to altered gene expression. Moreover, such epigenetic alterations may be vertically transferred to offspring . Environmental factors such as winter-spring births, perinatal infections, household crowding, upbringing in urban areas, and pet ownership support the concept that schizophrenia could be triggered by infectious agents affecting the brains of genetically susceptible individuals , , , , .
Retroviruses are candidate infectious agents in CNS diseases of unknown etiology because of their neurotropism and latency (reviewed in , ). In particular human endogenous retroviruses (HERVs) have been repeatedly associated with schizophrenia and other neurological diseases (reviewed in ). HERVs are natural components of the human genome constituting at least 8% of human DNA. They are considered remnants of ancient germ line infections by exogenous retroviruses that have been genetically fixed and transmitted in a Mendelian fashion , . During evolution, these elements were amplified and spread throughout the genome by repeated events of retrotransposition and/or reinfection. To date, they comprise about 500,000 elements . Efficient cellular mechanisms have evolved to restrict their intracellular activities, including epigenetic mechanisms such as DNA methylation and chromatin remodeling, as well as posttranscriptional processing and RNA interference , , . However, at least some members of most HERV groups were found to be still transcriptionally active in a tissue-specific manner , .
In brain samples, cerebrospinal fluid and blood of patients with schizophrenia and schizoaffective disorders elevated levels of transcripts and/or proteins from at least three HERV groups, HERV-W, ERV9 and HERV-K(HML-2), have been repeatedly detected , , , , , , . This suggests failure of the cellular control mechanisms leading to activation or upregulation of distinct HERV elements in schizophrenia.
However, most schizophrenic patients had obtained antipsychotic medication for years , , , . Even first episode patients or patients with resent-onset schizophrenia were on medication for at least one or more weeks prior study intake , , . Therefore, irrespective to the question whether the observed alterations in HERV activity are causative or a consequence of the disease, a severe imponderability in appraising experimental data is the treatment of patients with neuroleptics and/or antidepressants known to influence gene expression by inducing epigenetic modifications , . Thus, the question arises whether the overrepresentation of certain HERV transcripts in brain tissue from patients with schizophrenia may be due to the effects of drugs rather than to the disease.
To address the potential impact of medication on HERV activity we analyzed the HERV...