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

Li Q, Cheung C, Wei R, Hui ES, Feldon J, Meyer U, Chung S, Chua SE, Sham PC, Wu EX, McAlonan GM - PLoS ONE (2009)

Bottom Line: 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.Identical immune challenge in late gestation resulted in significant expansion of 4(th) ventricle volume but did not disrupt sensorimotor gating.The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.

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.

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Related in: MedlinePlus

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.
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pone-0006354-g001: 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.

Mentions: The volumetric analyses of in-vivo MRI data showed that prenatal immune activation in early (GD9) or late (GD17) gestation did not significantly change total brain volume (F(2,19) = .162, p<.851), grey matter (F(2,19) = .017, p<.98) or white matter volume (F(2,19) = .136, p<.87) relative to prenatal control treatment. However, the application of VBM to map the volume of CSF showed greater CSF volumes in the lateral ventricles of offspring exposed to MIA on GD9 compared to control offspring (Figure 1). Importantly, the impact of prenatal immune challenge on CSF volumes in the lateral ventricles was clearly restricted to MIA in early gestation because no significant changes in lateral ventricular CSF volumes were apparent in offspring exposed to MIA in late gestation (i.e., on GD17) relative to controls (Figure 1). Instead VBM indicated an expansion in 4th ventricle volume in offspring exposed to prenatal challenge in late gestation. ANOVA of region of interest measures supported this effect of prenatal treatment on lateral ventricle volume (F(2,19) = 5.39, p<.01) and subsequent post-hoc analyses confirmed lateral ventriculomegaly in offspring exposed to MIA on GD9 relative to control offspring (see Tables 1, 2 and Figure 1).


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

Li Q, Cheung C, Wei R, Hui ES, Feldon J, Meyer U, Chung S, Chua SE, Sham PC, Wu EX, McAlonan GM - PLoS ONE (2009)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2710518&req=5

pone-0006354-g001: 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.
Mentions: The volumetric analyses of in-vivo MRI data showed that prenatal immune activation in early (GD9) or late (GD17) gestation did not significantly change total brain volume (F(2,19) = .162, p<.851), grey matter (F(2,19) = .017, p<.98) or white matter volume (F(2,19) = .136, p<.87) relative to prenatal control treatment. However, the application of VBM to map the volume of CSF showed greater CSF volumes in the lateral ventricles of offspring exposed to MIA on GD9 compared to control offspring (Figure 1). Importantly, the impact of prenatal immune challenge on CSF volumes in the lateral ventricles was clearly restricted to MIA in early gestation because no significant changes in lateral ventricular CSF volumes were apparent in offspring exposed to MIA in late gestation (i.e., on GD17) relative to controls (Figure 1). Instead VBM indicated an expansion in 4th ventricle volume in offspring exposed to prenatal challenge in late gestation. ANOVA of region of interest measures supported this effect of prenatal treatment on lateral ventricle volume (F(2,19) = 5.39, p<.01) and subsequent post-hoc analyses confirmed lateral ventriculomegaly in offspring exposed to MIA on GD9 relative to control offspring (see Tables 1, 2 and Figure 1).

Bottom Line: 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.Identical immune challenge in late gestation resulted in significant expansion of 4(th) ventricle volume but did not disrupt sensorimotor gating.The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.

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.

Show MeSH
Related in: MedlinePlus