Prenatal exposure of mice to a maternal immune challenge leads to brain MRI and behavioural changes in the offspring relevant to schizophrenia

Abstract

Summary: Maternal infection during pregnancy increases risk of serious psychiatric disorders in the offspring such as schizophrenia and autism, in the offspring. In clinical populations environmental influences are implicated in the development of ventriculomegaly in schizophrenia, the most consistent brain marker for schizophrenia in man. Using voxel-based and region-of-interest analysis of in-vivo MRI in a nouse model we found that maternal immune activation during pregnancy is an environmental risk factor for ventricular enlargement in offspring. Introduction: Epidemiology and experimental evidence supports a role for maternal immune activation during pregnancy in neurodevelopmental disorders such as schizophrenia and autism. However, the timing of such prenatal exposure appears to critically determine outcomes, with earlier exposure potentially triggering more severe behavioural phenotype in the offspring, relevent to schizophrenia. Ventriculomegaly is one of the most consistent findings in schizophrenia and is associated with the clinical condition rather than genetic factors shared with high risk relatives. We directly tested the hypothesis that maternal immune activation during pregnancy is an environmental risk factor for ventricular enlargement in a mouse model. In addition we tested whether impairment in sensorimotor gating, an endophenotype of schizophrenia, would accompany brain morphological changes. Materials and methods: We used a mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. In a novel application of automated voxel-based morphometry (VBM) of in-vivo MRI data, we mapped cerebrospinal fluid across the whole brain. The approach was validated using a manual region-of-interest tracing of lateral ventricles. We evaluated the behavioural impact of the prenatal exposure using the prepulse inhibition paradigm in the same mice and a sub-group previously un-scanned. Results: Manual region-of-interest tracing of lateral ventricles confirmed that the ventricular volumes segmented using automated methods closely overlapped with manually identified volumes (Dice co-efficient=0.93). Maternal immune activation, in early but not late gestation, caused significant enlargement of lateral ventricles in adulthood. This early exposure disrupted prepulse inhibition. Immune challenge in late gestation caused significant expansion of 4th ventricle volume but not prepulse inhibition deficit. Conclusion: Our findings lend direct support to the hypothesis that early prenatal immune activation exerts a more extensive neurodevelopmental impact in terms of schizophrenia-related brain and behavioral abnormalities compared with immunological insults taking place later in gestation. Such effects are potentially modifiable and deserve close attention in the context of the wider schizophrenia-autism spectrum.