Limits...
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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2710518&req=5

pone-0006354-g002: 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.

Mentions: In this test, a reduction of startle reactivity to the pulse stimulus on prepulse-plus-pulse trials relative to pulse-alone trials constitutes the PPI effect. The analysis of percent PPI (% PPI) confirmed that offspring exposed to MIA on GD9 but not on GD17 displayed reduced sensorimotor gating relative to control offspring (Figure 2). A 3×3×3 (group×prepulse intensity×pulse intensity) repeated measures ANOVA showed a significant effect of prepulse intensity [F(2, 131) = 11.87, p<0.0001] and a significant group difference in %PPI [F(2, 131) = 3.56, p<0.05]. There was also a significant interaction between pulse intensity and group [F(4, 262) = 4.32, p<0.01]. Subsequent post-hoc tests verified that the overall group difference in %PPI was driven by a significant impairment in PPI in the GD9 PolyI:C compared to control group (p<0.05). This PPI deficit in GD9 PolyI:C animals was evident in the pulse 100 and pulse 120 conditions (p<0.05). There was no difference in %PPI between GD17 PolyI:C and control groups (Figure 2). There were no significant group differences in startle reactivity, startle habituation or prepulse-elicited reactivity (data not shown). Hence, the PPI attenuating effects of prenatal PolyI:C exposure in early gestation cannot be accounted for by changes in general startle reactivity and/or prepulse detection, reflecting a genuine disruption of sensorimotor gating.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006354-g002: 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.
Mentions: In this test, a reduction of startle reactivity to the pulse stimulus on prepulse-plus-pulse trials relative to pulse-alone trials constitutes the PPI effect. The analysis of percent PPI (% PPI) confirmed that offspring exposed to MIA on GD9 but not on GD17 displayed reduced sensorimotor gating relative to control offspring (Figure 2). A 3×3×3 (group×prepulse intensity×pulse intensity) repeated measures ANOVA showed a significant effect of prepulse intensity [F(2, 131) = 11.87, p<0.0001] and a significant group difference in %PPI [F(2, 131) = 3.56, p<0.05]. There was also a significant interaction between pulse intensity and group [F(4, 262) = 4.32, p<0.01]. Subsequent post-hoc tests verified that the overall group difference in %PPI was driven by a significant impairment in PPI in the GD9 PolyI:C compared to control group (p<0.05). This PPI deficit in GD9 PolyI:C animals was evident in the pulse 100 and pulse 120 conditions (p<0.05). There was no difference in %PPI between GD17 PolyI:C and control groups (Figure 2). There were no significant group differences in startle reactivity, startle habituation or prepulse-elicited reactivity (data not shown). Hence, the PPI attenuating effects of prenatal PolyI:C exposure in early gestation cannot be accounted for by changes in general startle reactivity and/or prepulse detection, reflecting a genuine disruption of sensorimotor gating.

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