Human Endogenous Retrovirus as Missing Link in the Global Etiopathogenesis of Schizophrenia and Bipolar Disorder

Schizophrenia (SZ) and bipolar disorder (BD) involve complex interactions between genetic and environmental factors, but underlying mechanisms are poorly understood. This review explains how human endogenous retroviruses (HERVs) may provide a missing link between environmental factors, genomics, and pathogenic pathways leading to clinical expression. HERVs represent a disregarded part of the human genome resulting from endogenization of retroviruses during evolution. HERVs can be activated by environmental triggers such as infectious agents. Elevated HERV-W transcriptional activity or HERV-W ENV antigenemia were reported in patients with SZ or BD. A recent study showed that HERV-W ENV affected synaptic surface dynamics of glutamatergic receptors and that psychotic behavior was induced in an animal model expressing HERV-W ENV protein in hippocampal neurons. A specific antibody targeting HERV-W ENV inhibited HERV-W ENV pathogenic effects in vitro and prevented abnormal behavioral signs in vivo. A lifelong scenario of interactions between environmental pathogens and HERV-W genes is now presented, which may decipher the actual development and course of such diseases. New therapeutic strategies targeting pathogenic and nonphysiological agonists are also suggested, which may allow treating or possibly preventing SZ or BD without impairing physiological functions.