AN ANIMAL MODEL OF CHRONIC PLACENTAL INSUFFICIENCY: RELEVANCE TO NEURODEVELOPMENTAL DISORDERS INCLUDING SCHIZOPHRENIA A. E. REHN, a,b M. VAN DEN BUUSE, b,d D. COPOLOV, b T. BRISCOE, a G. LAMBERT c AND S. REES a * a Department of Anatomy and Cell Biology, The University of Mel- bourne, Grattan Street, Parkville, Victoria, 3010, Australia b Mental Health Research Institute of Victoria, Parkville, Victoria, 3052, Australia c Baker Medical Heart Research Institute, Commercial Road, Mel- bourne, Victoria 3004, Australia d Department of Pharmacology, University of Melbourne, Melbourne, Victoria, 3010, Australia Abstract—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 preg- nancy, 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 schizo- phrenia. 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 unilat- eral 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 immunohistochem- ical markers. In a separate cohort of animals, prepulse inhibi- tion (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, re- duced 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 impair- ment of PPI is comparable to sensorimotor gating deficits ob- served 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. © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: lateral ventricles, dopamine, prepulse inhibition, neurodevelopmental hypothesis, hippocampus, brain devel- opment. Several lines of evidence now suggest that abnormal brain development in utero may be a risk factor for the manifes- tation of neurological disorders including schizophrenia (Akil and Weinberger, 2000), in later life. While several animal models have been generated in an attempt to in- duce changes in the brain and behavior similar to those observed in human schizophrenia (Lipska et al., 1995; Mohn et al., 1999; Talamini et al., 1999), they do not mimic specific events that are known to occur during gestation. We have developed a guinea-pig model which mimics a situation which can occur in pregnant women, namely chronic placental insufficiency. This can result from mater- nal smoking, hypertension, placental villus edema or dam- age to the placenta or uterine arteries (Naeye et al., 1989). In the guinea-pig, restricted uteroplacental blood flow via unilateral ligation of the uterine artery produces fetuses and neonates that are growth-restricted, chronically hy- poxic (Lafeber et al., 1984), hypoglycaemic (Jones and Parer, 1983), and have an altered endocrine balance (Jones et al., 1987) and altered brain development both at term (Nitsos and Rees 1990; Mallard et al., 1999) and in the early postnatal period (Mallard et al., 2000). Interest- ingly, many of the alterations in brain structure that we have described (Mallard et al., 1999) are similar to the changes identified in some patients with schizophrenia, including ventriculomegaly (Jaskiw et al., 1994), reduced brain (Harrison et al., 2003) and birth (Cannon et al., 2002) weight and a reduction in hippocampal cornu ammonis area 1 (CA1) pyramidal cell numbers (Benes et al., 1991). To investigate the validity of the hypothesis that ad- verse prenatal events are risk factors for the neuropathol- ogies and behavioral alterations associated with schizo- phrenia, it was important to determine whether the changes that we have identified perinatally (Mallard et al., 1999, 2000) persist in the long term. Therefore, in the present study we have tested two hypotheses: firstly, that a prenatal insult in the form of chronic placental insuffi- ciency has long-term structural and neurochemical effects in the guinea-pig brain in regions or pathways which could be relevant to the abnormalities in the brains of patients *Corresponding author. Tel: +61-3-8344-5797; fax: +61-3-9347- 5219. E-mail address: s.rees@unimelb.edu.au (S. Rees). Abbreviations: ANOVA, analysis of variance; BDNF, brain-derived neurotrophic factor; CA1, cornu ammonis area 1; DAB, 3,3=-diamino- benzidine; DAT, dopamine transporter; DOPAC, dihydroxyphenylac- etic acid; GFAP, glial fibrillary acidic protein; HPLC, high performance liquid chromatography; IGF, insulin-like growth factor; IR, immunore- active; PB, phosphate buffer; PC, prenatally compromised; PFA, para- formaldehyde; PPI, prepulse inhibition. Neuroscience 129 (2004) 381–391 0306-4522/04$30.00+0.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.07.047 381