Elsevier

Brain, Behavior, and Immunity

Volume 26, Issue 8, November 2012, Pages 1288-1299
Brain, Behavior, and Immunity

Behaviour and hippocampus-specific changes in spiny mouse neonates after treatment of the mother with the viral-mimetic Poly I:C at mid-pregnancy

https://doi.org/10.1016/j.bbi.2012.08.011Get rights and content

Abstract

Epidemiological studies have suggested a link between prenatal exposure to bacterial or viral infections and subsequent development of mental disorders such as schizophrenia and autism. Animal models to study the prenatal origin of such outcomes of pregnancy have largely used conventional rodents which are immature at birth compared to the human neonate, and doses of the infective agent (i.e., lipopolysaccharide, Poly I:C) have been large enough to cause sickness behaviour in the mother. In this study we have used the spiny mouse (Acomys cahirinus) whose offspring have completed organogenesis at birth, and a single subcutaneous injection of a low (0.5 mg/kg) dose of polyriboinosinic–polyribocytidilic acid (Poly I:C) at mid gestation (20 days, term is 39 days). The treatment had no effect on maternal, fetal or neonatal survival, or postnatal growth of the offspring. However, offspring showed significant impairments in non-spatial memory and learning tasks, and motor activity. Brain histology examined at 1 and 100 days of age revealed significant decreases in reelin, increased GFAP expression, and increased numbers of activated microglia, specifically in the hippocampus. This study provides evidence that a prenatal subclinical infection can have profound effects on brain development that are long-lasting.

Highlight

► Behavioural deficits and neurological abnormalities in spiny mouse offspring prenatally exposed to the viral-mimetic Poly I:C.

Introduction

Epidemiological evidence indicates a link between prenatal exposure to influenza (Brown et al., 2000a, Brown et al., 2000b), rubella (Brown et al., 2004a), toxoplasmosis (Brown et al., 2005), herpes simplex virus type 2 (Buka et al., 2001), measles (Fuller Torrey et al., 1988) and varicella zoster (Fuller Torrey et al., 1988) and the development of mental illness disorders such as schizophrenia and autism in later life. It has been suggested that the exact identity of the pathogen may not be the critical factor in the disruption of fetal brain development and the appearance of behavioural disorders in postnatal life. Thus, somewhat similar changes of maternal cytokines occur in response to various infections, and this is thought to be the key underlying mechanism that disturbs brain development (Ashdown et al., 2006, Brown, 2006, Brown et al., 2004b, Gilmore and Jarskog, 1997, Meyer et al., 2009).

Based on this epidemiological and immune system evidence, animal studies have sought to validate the link between prenatal infection and the dysfunction of behaviour and cognition in later life. Polyriboinosinic–polyribocytidilic acid (Poly I:C) is synthetic double stranded ribonucleic acid that is recognised by the innate immune receptor toll-like receptor (TLR)-3. Poly I:C is often referred to as a viral mimetic as it activates the immune system and produces dose-dependent cytokine responses comparable to those occurring during naturally-occurring, opportunistic viral infections (Cunningham et al., 2007, Fortier et al., 2004, Gilmore et al., 2005, Meyer et al., 2005). Numerous in vivo models using Poly I:C administration during pregnancy in conventional rodents have established that behaviour in the offspring is altered, with some similarities to the abnormal behaviours observed in infants and children following viral infection in human pregnancy (De Miranda et al., 2010, Howland et al., 2012, Makinodan et al., 2008, Meyer et al., 2005, Ozawa et al., 2006, Schwendener et al., 2009, Wolff and Bilkey, 2008, Zuckerman et al., 2003, Zuckerman and Weiner, 2005).

A limitation of these previous studies is worth noting. Conventional rats and mice are immature at birth, with significant structural and functional development of the brain occurring in the first weeks of postnatal life; hence, the effects of treatments given during rodent pregnancy do not appropriately reflect the changes likely to occur during fetal development in human pregnancy. Therefore, in this study we chose to study the spiny mouse (Acomys cahirinus) where the longer gestation (38–39 days), and small litter size (1–4, usually 3) result in the birth of developmentally more mature offspring (Dickinson et al., 2005). Compared to other rodents, where the development of the major organs continue into neonatal life, maturation of the kidney (Dickinson et al., 2005), lung (Oosterhuis et al., 1984), liver (Lamers et al., 1985) and the brain (Brunjes et al., 1989) of the spiny mice occurs primarily in utero.

Previous studies administered high doses of Poly I:C (5 mg/kg) intravenously or intraperitoneally, which produce significant sickness behaviours and a febrile response in the pregnant dam (Meyer et al., 2005, Meyer et al., 2006a). However, little attention has been given to modelling common subclinical infections such as the common cold, for which a pregnant women is less likely to seek treatment or advice. The present study was designed to determine if a low dose of Poly I:C given to pregnant spiny mice had long-term effects on the behaviour and the neurological outcome of their offspring. As human epidemiological (Brown et al., 2004a, Brown et al., 2004b, Kendell and Kemp, 1989, Machon et al., 2002, Mednick et al., 1988, Suvisaari et al., 1999) and animal studies (Meyer et al., 2006b, Meyer et al., 2008b) suggest that activation of the maternal immune system in the second trimester is a critical risk factor for the emergence of abnormal behaviours in later life, we chose mid-gestation to deliver the Poly I:C treatment in the pregnant spiny mouse.

Section snippets

Animals

Spiny mice (A. cahirinus) were obtained from the breeding colony maintained at Monash Medical Centre and bred and housed as previously described (Dickinson ANZCCART). Notably, spiny mice were housed at a constant temperature of 25 ± 0.5 °C, constant humidity of 30 ± 5% and a 12 h light-dark cycle (lights on at 0700 h). Food and water were available ad libitum. Experiments were conducted in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. All

Organ and body weights

There was no significant difference in maternal weight between PBS and Poly I:C administered dams at 24 h after administration (Table 1). There was a significant effect of Poly I:C administration on placental weight at 24 h after administration, with a significant reduction in Poly I:C placentas compared to PBS (p = 0.017), although when fetal weight was taken into account, there was no significant difference between the treatment groups in placenta to fetal weight ratio (p = 0.872, Table 1). There

Discussion

In this study we show that injecting pregnant spiny mice with a single low dose of synthetic viral mimetic Poly I:C has long lasting effects on behaviour and neurological outcome of the offspring. The dose we used, 0.5 mg/kg, was one-tenth of that commonly used in other studies, and did not cause any signs of illness or abnormal behaviour in the pregnant dam. In addition, in using the spiny mouse at mid-gestation, the fetuses remained in the maternal and uterine environment during the time that

Conclusion

This study suggests a lower dose of Poly I:C during pregnancy causes unique behaviour deficits in learning and memory and locomotor activity in spiny mice offspring. Based solely on the behavioural outcome of the offspring and comparisons with previous studies in conventional rodents, we are not able to conclude that our model is an appropriate neurodevelopmental animal model of schizophrenia and autism without further behavioural assessment. Other then dose, disparity in results may be also

Acknowledgments

This research has been undertaken in the authors’ capacity as a staff member, student or affiliate of Monash Institute of Medical Research, Monash University. This work is supported by funding from the ANZ Trustees, National Health and Medical Research Council and the Victorian Government’s Operational Infrastructure Support Program.

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