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The Hypoxic Rat Model for Obstetric Complications in Schizophrenia

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Animal Models of Schizophrenia and Related Disorders

Part of the book series: Neuromethods ((NM,volume 59))

Abstract

Hypoxia has been discussed as a possible factor of obstetric complications in the pathophysiology of schizophrenia. This study investigated the effects of chronic neonatal hypoxia in rats as an animal model of schizophrenia. Methods: (1) After chronic neonatal hypoxia between postnatal day (PD) 4 and 8, half of the pups were fostered by normally treated nurse animals to control for possible maternal effects and (2) tested on PD 36, 86, 120, and 150 using three different behavioral tests: prepulse inhibition (PPI), social interaction and recognition, and motor activity in an open field. (3) Before the PD 150 test, 50% of the animals had been chronically treated with the antipsychotic drug clozapine (45 mg/kg/day). (4) At PD 155, different brain regions have been used for expression profiling of synaptic genes on cDNA microarrays (“glutamate chip”) with qRT-PCR confirmation. Additionally, at PD 11 and 120, NMDA receptor binding and expression of NMDA receptor subunits have been performed. Rats exposed to hypoxia exhibited deficits in locomotor activity on PD 86, 120, and 150, as well as a PPI deficit on PD 120 and 150 in adulthood, but not before. Chronic treatment with clozapine reversed hypoxia-induced PPI deficits, but not the decreased locomotor activity. In a second experiment, where clozapine was chronically administered before PD 120, development of the PPI deficit in the animals exposed to hypoxia was prevented. In several brain regions, presynaptic genes such as SNAP-25, syntaxin 1A, neurexin, neuropeptide Y, and complexin I were downregulated and the NR1 subunit of the NMDA receptor was upregulated by hypoxia. These differential gene regulations could be partially compensated for by clozapine treatment. NMDA receptor binding was decreased at PD 11 and expression of the NR1 subunit was increased at PD 11 and 120. The time course of hypoxia-induced PPI deficits and their reversal by clozapine support the validity of our animal model and the hypothesis that hypoxia as a factor of obstetric complications plays a role in the pathophysiology of schizophrenia. Differential gene expression in cortical and subcortical brain regions as well as correlations to deficits of PPI support the view of an involvement of synapse-associated gene products and glutamatergic and GABAergic neurotransmission in the pathophysiology of behavioral deficits occurring as delayed responses to neonatal hypoxia in adulthood.

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Authors and Affiliations

  1. Department of Psychiatry, University of Goettingen, Goettingen, Germany

    Andrea Schmitt & Peter Falkai

  2. The Central Institute of Mental Health, Mannheim, Germany

    Peter Gebicke-Haerter, Ulrich Sommer, Markus Heck & Mathias Zink

  3. Faculty of Biology, University of Tubingen, Tubingen, Germany

    Anja Lex & Markus Fendt

  4. Facultad de Medicina, Universidad de Chile, Santiago, Chile

    Mario Herrera-Marschitz

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  1. Andrea Schmitt
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  2. Peter Gebicke-Haerter
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  7. Mathias Zink
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  1. School of Medicine, Depts. of Anatomy & Neurobiology, University of Maryland, Penn St. 20, Baltimore, 21201, Maryland, USA

    Patricio O'Donnell

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Schmitt, A. et al. (2011). The Hypoxic Rat Model for Obstetric Complications in Schizophrenia. In: O'Donnell, P. (eds) Animal Models of Schizophrenia and Related Disorders. Neuromethods, vol 59. Humana Press. https://doi.org/10.1007/978-1-61779-157-4_4

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