Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: evidence from MRI in a mouse model

Abstract

Objectives: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood.

Method: We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities.

Results: PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4(th) ventricle volume but did not disrupt sensorimotor gating.

Conclusions: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

Figure 1. CSF space quantified using VBM and ROI methodology.

a. Overlap in lateral ventricles quantified using voxel-based morphometry (VBM) and region-of-interest (ROI) methodology showing an animal with the lowest agreement (Dice = 0.92 both sides) between the manual delineation and automatic segmentation of ventricles. Left ventricle in grey; right ventricle in white. b. Region-of-Interest defined lateral ventricles. Raw images and the 3D rendered lateral ventricles of a mouse from the control and one from the GD9 group. c. Voxel-wise analyses of CSF in adult mice exposed to prenatal challenge at GD9 compared to control and GD17 compared to control. Red indicates a significantly greater likelihood of finding CSF; Blue indicates a significantly lower likelihood of finding CSF.

Figure 2. Prepulse inhibition of startle.

Behavioral tests in mouse exposed to maternal immune activation at gestation day 9 or 17 (GD9 POL; GD17 POL) compared to controls (CON). Prepulse inhibition of startle (PPI). % PPI =  (pulse-alone - prepulse-plus-pulse)/pulse-alone×100%. A gradual increase in the amount of inhibition was observed as a function of the increasing intensity of the prepulse stimulus. All values are means±SEM.

Figure 3. Average T2 image and segmented tissue maps of all the mice used in this study.