Molecular mechanisms and timing of cortical immune activation in schizophrenia.

Abstract

Immune-related abnormalities are commonly reported in schizophrenia, including higher mRNA levels for the viral restriction factor interferon-induced transmembrane protein (IFITM) in the prefrontal cortex. The authors sought to clarify whether higher IFITM mRNA levels and other immune-related disturbances in the prefrontal cortex are the consequence of an ongoing molecular cascade contributing to immune activation or the reflection of a long-lasting maladaptive response to an in utero immune-related insult. Quantitative polymerase chain reaction was employed to measure mRNA levels for immune-related cytokines and transcriptional regulators, including those reported to regulate IFITM expression, in the prefrontal cortex from 62 schizophrenia and 62 healthy subjects and from adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant poly(I:C). Schizophrenia subjects had markedly higher mRNA levels for interleukin 6 (IL-6) (+379%) and interferon-β (+29%), which induce IFITM expression; lower mRNA levels for Schnurri-2 (-10%), a transcriptional inhibitor that lowers IFITM expression; and higher mRNA levels for nuclear factor-κB (+86%), a critical transcription factor that mediates cytokine regulation of immune-related gene expression. In adult mice that received daily poly(I:C) injections, but not in offspring with prenatal exposure to maternal immune activation, frontal cortex mRNA levels were also markedly elevated for IFITM (+304%), multiple cytokines including IL-6 (+493%), and nuclear factor-κB (+151%). These data suggest that higher prefrontal cortex IFITM mRNA levels in schizophrenia may be attributable to adult, but not prenatal, activation of multiple immune markers and encourage further investigation into the potential role of these and other immune markers as therapeutic targets in schizophrenia.