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


METHODS
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.
Li
Qi
Q
Department of Psychiatry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
Cheung
Charlton
C
Wei
Ran
R
Hui
Edward S
ES
Feldon
Joram
J
Meyer
Urs
U
Chung
Sookja
S
Chua
Siew E
SE
Sham
Pak C
PC
Wu
Ed X
EX
McAlonan
Grainne M
GM
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D012307:Risk Factors; D012559:Schizophrenia / Q000276:immunology* / Q000473:pathology