An animal model of chronic placental insufficiency: Relevance to neurodevelopmental disorders including schizophrenia

Evidence now suggests that compromised prenatal brain development may increase the risk for the manifestation of neurological disorders such as schizophrenia. We present a guinea-pig model which mimics a condition of human pregnancy, namely, chronic placental insufficiency. Previously we reported that at term there are changes in the brains of these offspring which are relevant to changes in patients with schizophrenia. The aim of this study was to examine whether deficits in brain structure persist to adolescence and young adulthood (8-12 weeks) and have implications for behavioral function. Reduced uteroplacental blood flow was induced via unilateral ligation of the uterine artery at mid-gestation. The brain was examined in control and prenatally compromised (PC) animals 8 weeks after birth using morphometric and immunohistochemical markers. In a separate cohort of animals, prepulse inhibition (PPI) of the acoustic startle response was assessed at 4, 8 and 12 weeks of age. Brain neurochemistry was examined by determining the concentrations of dopamine and its metabolite, dihydroxyphenylacetic acid (DOPAC), at 12 weeks using high performance liquid chromatography. In PC animals compared with controls there was a reduction in brain weight, persistent enlargement of the lateral ventricles, a reduction in the volume of the basal ganglia and septal region and no evidence of gliosis. No differences were observed in concentration of catecholamines in any brain region examined. At 12, but not 4 or 8, weeks of age, PPI was reduced in PC animals compared with controls. The findings of reduced brain weight, ventriculomegaly, reduced basal ganglia volume and absence of astrogliosis in the PC guinea-pig brain at adolescence parallel some of the changes observed in patients with schizophrenia. The impairment of PPI is comparable to sensorimotor gating deficits observed in patients with schizophrenia. These results indicate that adverse prenatal conditions lead to long-term alterations in brain structure and function which resemble alterations seen in patients with schizophrenia and therefore support the early neurodevelopmental hypothesis of schizophrenia. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.