ReviewEffects of prenatal infection on brain development and behavior: A review of findings from animal models
Introduction
Epidemiological studies in humans have provided substantial evidence that prenatal infection is associated with an increased risk for the development of several psychiatric and neurologic disorders, most prominently schizophrenia, autism and cerebral palsy. While these associations provide rationale for suggesting that prenatal infection might contribute to the cause of these disorders, they do not prove causation. Animal modeling provides an opportune approach to ask if prenatal infection can actually cause transient or lasting changes in CNS function, and what the mechanisms for this might be. Since 2000, there has been a veritable explosion of studies from various laboratories that have used in vivo animal modeling, mainly in rodents, to characterize effects of systemic prenatal infection on brain development and behavior. The aim of this review is to provide a comprehensive overview of these findings from animal models of prenatal infection, in an effort to tease out consistencies, trends and deficiencies in the literature and to suggest possibilities for future directions.
In order to understand directions these animal modeling studies have taken, I will first provide a short introduction to the epidemiological literature associating prenatal infections with increased risk for CNS disorders in humans, although it is not the purpose of this paper to review this area in depth. An extensive literature has described that increased risk for schizophrenia is associated with a history of prenatal infection with a wide variety of different infectious agents (reviewed by Brown and Derkits, 2010). First reported by Mednick et al. (1988) in the mid-1980s, numerous groups (although not all) have replicated the finding that maternal influenza during pregnancy is associated with an increased incidence of schizophrenia (Barr et al., 1990, O’Callaghan et al., 1991, Sham et al., 1992, Adams et al., 1993, Mednick et al., 1994, Takei et al., 1996, Battle et al., 1999, Munk-Jorgensen and Ewald, 2001, Limosin et al., 2003, Brown et al., 2004, Ebert and Kotler, 2005, Byrne et al., 2007, Selten et al., 2009). Increased incidence of schizophrenia has also been associated with other viral infections (measles, rubella, varicella-zoster, polio, herpes simplex virus type 2), with bacterial infections (pneumonia and other respiratory infections, pyelonephritis, diverse bacterial infections) during pregnancy, with maternal infection with the toxoplasmosis parasite and with maternal genital/reproductive infections arising from various organisms (Torrey et al., 1988, O’Callaghan et al., 1994, Suvisaari et al., 1999, Brown et al., 2000, Brown et al., 2005, Brown and Susser, 2002, Babulas et al., 2006, Mortensen et al., 2007, Buka et al., 2008, Clarke et al., 2009, Sørensen et al., 2009). While most studies have relied on maternal recall and retrospective or prospective hospital records to assess maternal infections, recent studies assessing maternal infection via analysis of archived maternal serum have confirmed the association between prenatal viral infection and increased schizophrenia risk (Brown and Susser, 2002, Brown et al., 2004, Brown et al., 2005, Mortensen et al., 2007, Buka et al., 2008, Xiao et al., 2009). In more detailed recent studies examining symptom subsets in psychosis, Zammit et al. (2009) have reported a significant association between maternal infection during pregnancy and the presence of psychosis-like symptoms in adolescents at 12 years of age. Ellman et al. (2009) have reported that persons with schizophrenia and affective psychosis showed greater deficits in verbal IQ and other aspects of cognitive functioning prior to the onset of psychosis if they had been exposed prenatally to serologically confirmed influenza B. In a similar vein, Brown et al. (2009) documented that patients with schizophrenia who were exposed to serologically confirmed influenza or toxoplasmosis in utero showed greater deficits in cognitive tests of set-shifting ability, compared to patients not exposed to prenatal infection. As an additional aspect, Clarke et al. (2009) have recently reported that maternal pyelonephritis during pregnancy is associated with increased risk for schizophrenia only in persons with a positive family history of schizophrenia, suggesting a gene x environment interaction as the mechanism for increased schizophrenia risk.
With respect to timing of the infection, numerous studies have identified the 2nd trimester of pregnancy as the critical period for exposure to influenza and other viral infections, leading to increased schizophrenia (Torrey et al., 1988, O’Callaghan et al., 1994, Suvisaari et al., 1999, Brown et al., 2000, Ebert and Kotler, 2005). However, the most pronounced association of rubella infection with schizophrenia spectrum disorders was found with 1st trimester exposure (Brown and Susser, 2002). Moreover, a recent study confirming presence of influenza antibodies in archived maternal serum has described increased schizophrenia risk with exposure during the 1st third to half of pregnancy (Brown et al., 2004), while another recent study has associated increased schizophrenia with bacterial infection during the 1st trimester (Sørensen et al., 2009). Thus it appears that animal modeling of both viral and bacterial infection during the equivalent of the 1st and 2nd trimesters of human pregnancy may be relevant to the pathophysiology of schizophrenia.
Evidence implicating a role for prenatal infection in the etiology of autism is much less extensive. Two larger studies have reported increased incidence of autism following congenital rubella or maternal viral infection during pregnancy (Chess, 1977, Wilkerson et al., 2002), however, the trimester of increased vulnerability was not identified. Beyond this, several case reports have linked autism to prenatal exposure to various viruses, such as cytomegalovirus (Ciaranello and Ciaranello, 1995, Libbey et al., 2005). Increased risk for cerebral palsy has most often been associated with chorioamnionitis (i.e. intra-uterine infection), although there is some evidence that extra-uterine maternal infections during pregnancy may also play a role (Murphy et al., 1995, Clark et al., 2008). Meta-analysis has indicated a significant association between chorioamnionitis and cerebral palsy for both preterm and term infants (Wu and Colford, 2000, Wu, 2002).
Section snippets
Animal models of systemic prenatal infection
To date, animal modeling to assess effects of maternal infection during pregnancy on CNS function in offspring has been done almost exclusively using rats and mice. Both bacterial and viral infections during pregnancy have been modeled, using three main immunogenic approaches, namely, administration of lipopolysaccharide (LPS), influenza virus or polyinosinic:polycytidylic acid (poly IC) to the pregnant rodent. LPS or poly IC have been injected intraperitoneally, intravenously or
Acute effects of prenatal immune activation on fetal brain
Table 1 shows a summary of changes in fetal brain measured acutely (usually within 24 h) following administration of LPS or poly IC to pregnant rats or mice. Findings for placenta, amniotic fluid and other fetal tissues, that were reported in these studies, are also listed. The most often studied parameter has been cytokine expression in the fetal brain. Increased mRNA for IL-1β and also TNF-α or IL-6, in fetal brain has been reported by three groups following maternal LPS at E18 in the rat or
Behavioral changes in offspring after prenatal immune activation
The most frequently observed behavioral alteration in rodent offspring as a result of prenatal immune activation is a deficit in prepulse inhibition (PPI) of acoustic startle (see Table 2). In the rat, deficits in PPI in adult offspring have been reported following prenatal administration of either LPS or poly IC (Borrell et al., 2002, Fortier et al., 2004a, Fortier et al., 2007, Romero et al., 2007, Romero et al., 2010, Wolff and Bilkey, 2008). In the mouse, PPI deficits following prenatal
Morphological changes in brains of offspring after prenatal immune activation
Table 3 shows morphological changes measured several days to months after birth in the brains of offspring that had been exposed to prenatal immune activation. In response to prenatal LPS exposure, increases in cerebral cortical lesions characterized by shrunken neuronal cell bodies and nuclei (Larouche et al., 2005), increased ibotenate-induced cortical lesions (Rousset et al., 2008) and increased striatal apoptosis (Rousset et al., 2006) have been observed at early postnatal ages (P3–P9) in
Changes in neurotransmitter systems and CNS electrophysiology in offspring after prenatal immune activation
At the neurochemical level, neurotransmitter systems that have been examined following prenatal immune activation include dopamine (DA), serotonin (5-HT) and the amino acids, glutamate and GABA (Table 4). Ling, Carvey and colleagues have published a large series of studies in which they have repeatedly shown that prenatal exposure of rats to a relatively high dose of LPS on E10.5 results in decreased tyrosine hydroxylase (TH) immunoreactive neurons in dopaminergic cell body regions at various
Molecular changes in brains of offspring after prenatal immune activation
Table 5 lists additional long-term molecular changes observed in brains of offspring at various postnatal ages following prenatal immune activation. With prenatal administration of relatively high doses of LPS (>500 μg/kg) in rats (Table 5), at least two independent laboratories have observed increased levels of various markers of oxidative stress (Ling et al., 2004b, Ling et al., 2006, Zhu et al., 2007, Paintlia et al., 2008), increased cytokine levels (Ling et al., 2002, Ling et al., 2004a,
Timing
Prenatal immune activation at a specific time during pregnancy will impact on the particular developmental events occurring in fetal brain at that time. Thus delineating specific time windows in gestation during which prenatal immune activation alters specific CNS systems is an important first step to understand mechanisms mediating these effects. An optimum approach to investigate this issue is for immune activation at different gestational periods to be examined by a single laboratory in the
Discussion
Among the many reported findings on CNS changes due prenatal immune activation in rodents, several stand out because they have been independently described by more than one group. Acutely or at early ages after prenatal exposure to immunogens, changes indicative of oxidative stress and microglial activation have been found in brains of offspring. Increased levels of placental cytokines are consistently reported, suggesting that placental dysfunction could play a role in transducing acute
Conflict of interest statement
The author declares that there are no conflicts of interest.
Acknowledgment
I would like to thank the Canadian Institutes of Health Research for financial support.
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