Elsevier

Neuroscience

Volume 129, Issue 2, 2004, Pages 381-391
Neuroscience

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

https://doi.org/10.1016/j.neuroscience.2004.07.047Get rights and content

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 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.

Section snippets

Experimental procedures

All procedures were carried out under the approval of the University of Melbourne Animal Experimentation and Ethics Committee in accordance with the National Health and Medical Research Council of Australia and international guidelines. The number of experimental animals entered into this study was the minimum required to allow for statistical analysis to be performed for each parameter. All efforts were made to minimise pain and suffering of animals.

Body and brain weights

In PC (n=10) compared with control (n=10) animals at birth and at 8 weeks of age, there was a reduction in body weight (P<0.001) and crown to rump length (P<0.01). Whole brain (P<0.001), cerebellum (P<0.001) and brainstem weights (P<0.01) were reduced in PC animals; the brain to body weight ratio was not reduced (Table 1).

Structural analysis of the brain

Examination of Thionin-stained sections from PC brains did not reveal any gross malformations, infarcts or lesions. The volume of the lateral ventricles was greater in PC

Discussion

In this study we have tested the hypothesis that adverse prenatal conditions result in long term alterations to brain structure and function and that these deficits resemble changes reported for patients with schizophrenia. The strength of our model is that it mimics a situation that could occur in human pregnancy albeit at the more severe end of the spectrum of prenatal conditions. We have clearly demonstrated that guinea-pigs subjected to chronic placental insufficiency sustain long term

Acknowledgments

We are grateful to Dr. Sandra Dieni for assistance with the surgery. This work was supported by the National Health and Medical Research Council of Australia and the Mental Health Research Institute of Victoria, Australia. Dr. M. Van den Buuse is supported by a Griffith Senior Research Fellowship from the University of Melbourne.

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