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Altered prepulse inhibition of the acoustic startle response in BDNF-deficient mice in a model of early postnatal hypoxia: implications for schizophrenia

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Abstract

The brain-derived neurotrophic factor (BDNF) is a major proliferative agent in the nervous system. Both BDNF-deficiency and perinatal hypoxia represent genetic/environmental risk factors for schizophrenia. Moreover, a decreased BDNF response to birth hypoxia was associated with the disease. BDNF expression is influenced by neuronal activity and environmental conditions such as hypoxia. Thus, it may partake in neuroprotective and reparative mechanisms in acute or chronic neuronal insults. However, the interaction of hypoxia and BDNF is insufficiently understood and the behavioral outcome unknown. Therefore, we conducted a battery of behavioral tests in a classical model of chronic early postnatal mild hypoxia (10% O2), known to significantly impair brain development, in BDNF-deficient mice. We found selective deficits in measures associated with sensorimotor gating, namely enhanced acoustic startle response (ASR) and reduced prepulse inhibition (PPI) of ASR in BDNF-deficient mice. Unexpectedly, the alterations of sensorimotor gating were caused only by BDNF-deficiency alone, whereas hypoxia failed to evoke severe deficits and even leads to a milder phenotype in BDNF-deficient mice. As deficits in sensorimotor gating are present in schizophrenia and animal models of the disease, our results are of relevance regarding the involvement of BDNF in its pathogenesis. On the other hand, they suggest that the effect of perinatal hypoxia on long-term brain abnormalities is complex, ranging from protective to deleterious actions, and may critically depend on the degree of hypoxia. Therefore, future studies may refine existing hypoxia protocols to better understand neurodevelopmental consequences associated with schizophrenia.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (IN168/3-1), the Ingeborg Ständer Foundation and the Research Fund of the UPK Basel to D.I.

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  1. Juan M. Lima-Ojeda, Anne S. Mallien, Undine E. Lang, Dimitri Hefter, and Dragos Inta have contributed equally to this work.

Authors and Affiliations

  1. RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    Juan M. Lima-Ojeda, Anne S. Mallien, Christiane Brandwein, Dimitri Hefter & Dragos Inta

  2. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

    Juan M. Lima-Ojeda

  3. Department of Psychiatry (UPK), University of Basel, Wilhelm Klein-Strasse 27, 4012, Basel, Switzerland

    Undine E. Lang & Dragos Inta

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  1. Juan M. Lima-Ojeda
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Contributions

DI conceived and designed the experiments and contributed reagents/materials/analysis tools. UL contributed reagents/materials/analysis tools. JL and CB performed the experiments. JL, CB, AM and DH analyzed the data. DH, DI, AM and CB wrote the paper.

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Correspondence to Dragos Inta.

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Lima-Ojeda, J.M., Mallien, A.S., Brandwein, C. et al. Altered prepulse inhibition of the acoustic startle response in BDNF-deficient mice in a model of early postnatal hypoxia: implications for schizophrenia. Eur Arch Psychiatry Clin Neurosci 269, 439–447 (2019). https://doi.org/10.1007/s00406-018-0882-6

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