Prenatal Exposure to the Viral Mimetic Poly I:C Alters Fetal Brain Cytokine Expression and Postnatal Behaviour

Abstract

An increased incidence of mental illness disorders is found in children and adolescents born to mothers who experienced an infection-based illness during pregnancy. Animal models to study the prenatal origin of such outcomes of pregnancy have largely used conventional rodents, which are immature (altricial) at birth compared with the human neonate. In this study, we used the precocial spiny mouse (Acomys cahirinus), whose offspring have completed organogenesis at birth, and administered a single subcutaneous injection of a 5 mg/kg dose of the viral mimetic poly I:C (polyriboinosinic-polyribocytidylic acid) at mid gestation (20 days; term is 39 days). Prenatal exposure to poly I:C caused a transient weight loss in the pregnant dam, produced a downregulation of the proinflammatory cytokine tumour necrosis factor-α in the fetal brain, and resulted in abnormalities in sensorimotor gating and reduced social interaction, memory and learning in juvenile offspring. No changes in exploratory activity or anxiety and fear behaviours were found between the treatment groups. This study provides evidence that, in a rodent model that more closely resembles human brain development, prenatal infection can lead to behavioural abnormalities in postnatal life.

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

“…Antenatal infections are recognized as an important risk factor for adverse outcome in term and preterm neonates [27,28,29,30,31,32,33,34,35]. The combined exposure to perinatal inflammation and neonatal HI results in a complex interplay of various signaling pathways of which the exact underlying mechanism has not been elucidated yet.…”

A Critical Review of Models of Perinatal Infection

“…Similarly, in the spiny mouse ( Acomys cahirinus ), in which brain maturation at birth is relatively similar to term human infants, 5 mg/kg poly(I:C) at 20 days of gestation (term is 39 days) led to downregulation of tumor necrosis factor-α in the fetal brain, with behavioral abnormalities in sensorimotor function, social interaction, memory, and learning in the pups [42]. …”

Tumour necrosis factor-mediated homeostatic synaptic plasticity in behavioural models: testing a role in maternal immune activation

“…In the poly I : C model, an increase in IL-1b is observed in the fetal brain 24 h after maternal injection [94] but TNF in the fetal brain is actually decreased 24 h after maternal poly I : C injection [68] and also in the neonatal brain [34]. This may be a fetal mechanism to adapt to the maternal immune activation and occurs through a-and b-crystallin downregulation of TNF [67].…”

“…Importantly, previous studies have indicated that TNF does not play a role in the early transmission of inflammatory signalling to the fetus [66,67] before post-natal development. Additionally, in the poly I : C model, TNF levels are reported to decrease initially in the fetal brain [34,67,68]. Hence, if TNF-mediated plasticity regulates the neurodevelopment of the MIA offspring, then this regulation would likely occur after the animal was born.…”