Maternal poly I:C exposure during pregnancy regulates TNFα, BDNF, and NGF expression in neonatal brain and the maternal–fetal unit of the rat

Abstract

Maternal infection during pregnancy is associated with increased risk for neurodevelopmental disorders. Polyriboinosinic–polyribocytidilic acid (poly I:C) or saline was administered to rats to model maternal infection; levels of TNFα, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) were determined by ELISA. TNFα was significantly increased in maternal plasma, placenta, and amniotic fluid, while it was significantly decreased in fetal liver/spleen and neonatal brain. NGF and BDNF were significantly decreased in the placenta and fetal liver/spleen. There was no change in BDNF or NGF in the fetal or neonatal brain. Changes in TNFα, BDNF, and NGF after maternal exposure to poly I:C represent a potential mechanism through which maternal infection increases risk for neurodevelopmental disorders.

Introduction

Prenatal exposure to maternal infection is a risk factor for neurodevelopmental disorders, including schizophrenia (Brown et al., 2000), mental retardation (Rantakallio and Von Wendt, 1985), and autism (Ciaranello and Ciaranello, 1995). Little is known about the mechanism through which maternal infection acts on the developing brain to increase risk for these neurodevelopmental disorders. Because a variety of bacterial and viral maternal infections can increase risk, we have hypothesized that cytokines generated in response to infection represent a common mechanistic pathway through which early brain development is altered (Gilmore and Jarskog, 1997, Gilmore et al., 2004).

There have been several recent attempts to model the long-term consequences of maternal infection during pregnancy on behavior relevant to schizophrenia. These models include infection with human influenza virus (Shi et al., 2003), exposure to lipopolysaccharide (LPS), a bacterial cell wall endotoxin (Borrell et al., 2002, Fortier et al., 2004), and exposure to polyriboinosinic–polyribocytidilic acid (poly I:C), which mimics viral RNA (Shi et al., 2003, Zuckerman and Weiner, 2003, Zuckerman et al., 2003). These models suggest that maternally generated cytokines are likely mediators of the abnormal brain development that leads to long-term behavioral changes. In the influenza model, no virus is detected in the fetal brain (Shi et al., 2003), suggesting that the immune response to the infection plays a major role in the mechanism of action. In the poly I:C and LPS models, no infectious agent is present, implicating the cytokine response. Maternal LPS exposure does increase cytokine expression in the maternal blood, placenta, and amniotic fluid of rodents (Fidel et al., 1994, Urakubo et al., 2001, Gayle et al., 2004). There is increasing evidence of interactions between inflammatory cytokines and neurotrophins in the nervous system, and we have recently demonstrated that maternal LPS exposure also alters brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the developing brain and maternal–fetal unit (Gilmore et al., 2003). While poly I:C increases cytokine production by cells of the immune system (Kimura et al., 1994), the effect of poly I:C on cytokine or neurotrophic factor production during pregnancy is not known.

We studied the regulation of TNFα, BDNF, and NGF expression in maternal plasma, placenta, amniotic fluid, fetal liver/spleen, fetal brain, and neonatal cortex in a rodent model of maternal infection that utilizes poly I:C. We hypothesized that maternal exposure to poly I:C will regulate the expression of TNFα, BDNF, and NGF in a manner similar to that previously observed after maternal LPS exposure.