A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia.
ABSTRACT Prenatal exposure to infection is a significant environmental risk factor in the development of schizophrenia and related disorders. Recent evidence indicates that disruption of functional and structural dopaminergic development may be at the core of the developmental neuropathology associated with psychosis-related abnormalities induced by prenatal exposure to infection. Using a mouse model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, the present study critically evaluated this hypothesis by longitudinally monitoring the effects of maternal immune challenge during pregnancy on structural and functional dopaminergic development in the offspring from fetal to adult stages of life. Our study shows that prenatal immune challenge leads to dopaminergic maldevelopment starting as early as in the fetal stages of life and produces a set of postnatal dopaminergic abnormalities that is dependent on postnatal maturational processes. Furthermore, our longitudinal investigations reveal a striking developmental correspondence between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Prenatal immune activation thus appears to be a significant environmental risk factor for primary defects in normal dopaminergic development and facilitates the expression of postnatal dopamine dysfunctions involved in the precipitation of psychosis-related behavior. Early interventions targeting the developing dopamine system may open new avenues for a successful attenuation or even prevention of psychotic disorders following neurodevelopmental disruption of dopamine functions.
Article: Impaired executive function mediates the association between maternal pre-pregnancy body mass index and child ADHD symptoms.[show abstract] [hide abstract]
ABSTRACT: Increasing evidence suggests exposure to adverse conditions in intrauterine life may increase the risk of developing attention-deficit/hyperactivity disorder (ADHD) in childhood. High maternal pre-pregnancy body mass index (BMI) has been shown to predict child ADHD symptoms, however the neurocognitive processes underlying this relationship are not known. The aim of the present study was to test the hypothesis that this association is mediated by alterations in child executive function. A population-based cohort of 174 children (mean age = 7.3 ± 0.9 (SD) yrs, 55% girls) was evaluated for ADHD symptoms using the Child Behavior Checklist, and for neurocognitive function using the Go/No-go task. This cohort had been followed prospectively from early gestation and birth through infancy and childhood with serial measures of maternal and child prenatal and postnatal factors. Maternal pre-pregnancy BMI was a significant predictor of child ADHD symptoms (F((1,158)) = 4.80, p = 0.03) and of child performance on the Go/No-go task (F((1,157)) = 8.37, p = 0.004) after controlling for key potential confounding variables. A test of the mediation model revealed that the association between higher maternal pre-pregnancy BMI and child ADHD symptoms was mediated by impaired executive function (inefficient/less attentive processing; Sobel Test: t = 2.39 (± 0.002, SEM), p = 0.02). To the best of our knowledge this is the first study to report that maternal pre-pregnancy BMI-related alterations in child neurocognitive function may mediate its effects on ADHD risk. The finding is clinically significant and may extrapolate to an approximately 2.8-fold increase in the prevalence of ADHD among children of obese compared to those of non-obese mothers. These results add further evidence to the growing awareness that neurodevelopmental disorders such as ADHD may have their foundations very early in life.PLoS ONE 01/2012; 7(6):e37758. · 4.09 Impact Factor
Article: Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models.[show abstract] [hide abstract]
ABSTRACT: The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as 'Risk factors for schizophrenia--all roads lead to dopamine' or 'The dopamine hypothesis of schizophrenia--the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.Translational psychiatry. 02/2012; 2:e81.
Article: Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat.[show abstract] [hide abstract]
ABSTRACT: Environmental or genetic disturbances of early brain development are suggested to underlie the pathophysiology of several adult-onset neuropsychiatric disorders. We traced the developmental trajectories of brain structural and behavioral abnormalities from adolescence to young adulthood in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (poly-I:C) in pregnancy. Pregnant rats were injected on gestational day 15 with poly-I:C (4 mg/kg) or saline. Volumes of lateral ventricles, hippocampus, striatum, and prefrontal cortex in male and female offspring were assessed longitudinally at postnatal days 35, 46, 56, 70, and 90 using in vivo magnetic resonance imaging. At parallel time windows, groups of offspring from the same litters underwent behavioral testing (latent inhibition and amphetamine-induced activity) and magnetic resonance imaging (cross-sectional assessment). The specific developmental trajectories of volumetric changes in both control and poly-I:C offspring were region-, age-, and sex-specific, but overall, poly-I:C offspring had smaller volumes of the hippocampus, striatum and prefrontal cortex, and larger ventricular volume. Structural pathology in different regions had different times of onset and was gradually accompanied by behavioral deficits, disrupted latent inhibition, and excessive amphetamine-induced activity. The onset of structural frontocortical and ventricular abnormalities and behavioral abnormalities was delayed in females. In both sexes, hippocampal and striatal volume reduction predated the appearance of behavioral abnormalities. Prenatal insult interferes with postnatal brain maturation, which in turn may result in behavioral abnormalities.Biological psychiatry 08/2011; 70(9):842-51. · 8.93 Impact Factor