Die Wirkung von postnataler Hypoxie auf die neuronale Zellproliferation im Rattenhirn und ihre Relevanz für die Schizophrenie

Abstract

Neonatal hypoxia as a complication of pregnancy and birth is the most important predisposing environmental factor in the pathophysiology of schizophrenia. It leads to damage to the brain and the disruption of brain development. That said, to date the neurobiological effects of neonatal hypoxia especially on cell proliferation remain unclear. In animal experiments, behavioral changes similar to schizophrenia have been identified as emerging from chronic neonatal hypoxia. Disruptions in normal cell development could be the cause thereof. The hypothesis that the onset of abnormal brain development is perinatal while first clinical symptoms become manifest in early adulthood supports this conclusion. The early postnatal development of the brain of rats is comparable to that of the human fetus in the 3rd trimester of pregnancy and is therefore suitable for reflecting the pathological processes in the central nervous system of humans. In this study we investigated neuronal cell proliferation in 20 male Wistar rats at different times (postnatal day 13 and 39) with the help of postnatal hypoxia. The rats were exposed to a hypoxia consisting of 11% O2 and 89% N2 from postnatal day four to eight. Using a bromodeoxyuridine peroxidase assay, cell proliferation in hypoxia-vulnerable brain regions including the anterior cingulate cortex, the caudate putamen, the dentate gyrus and the subventricular zone was examined. An untreated control group served as a comparison. Using a step motor equipped microscope and stereo investigator software (MicroBrightField, UK) to apply the optical-fractionator method, it was possible to demonstrate for the first time that animals subjected to hypoxia showed a 20% increase in cell proliferation in the anterior cingulate cortex on postnatal day 13. Furthermore, the volume of the caudate putamen was reduced by 16% on postnatal day 13 in animals subjected to hypoxia. No further significant changes could be identified on postnatal day 39. These results show that it can be assumed that chronic hypoxia influences cell proliferation and that the brain seems to be tolerant within certain limits to exogenous noxae such as hypoxia during its neuronal development. The results also confirm that only a small part of the birth complications associated with hypoxia lead to schizophrenia and thus that the disease is the result of a mutifactorial gene-environment-interaction. With better knowledge of the neurobiological effects of environmental and genetic factors on the brain it might in future be possible to better anticipate and treat schizophrenia and reduce its disabling symptoms.