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Olfactory behavior and physiology are disrupted in prion protein knockout mice

Nature Neuroscience volume 12, pages 60–69 (2009)Cite this article

Abstract

The prion protein PrPC is infamous for its role in disease, but its normal physiological function remains unknown. Here we found a previously unknown behavioral phenotype of Prnp−/− mice in an odor-guided task. This phenotype was manifest in three Prnp knockout lines on different genetic backgrounds, which provides strong evidence that the phenotype is caused by a lack of PrPC rather than by other genetic factors. Prnp−/− mice also showed altered behavior in a second olfactory task, suggesting that the phenotype is olfactory specific. Furthermore, PrPC deficiency affected oscillatory activity in the deep layers of the main olfactory bulb, as well as dendrodendritic synaptic transmission between olfactory bulb granule and mitral cells. Notably, both the behavioral and electrophysiological alterations found in Prnp−/− mice were rescued by transgenic neuronal-specific expression of PrPC. These data suggest that PrPC is important in the normal processing of sensory information by the olfactory system.

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Figure 1: Impaired behavior of Zürich I Prnp−/− mice in the cookie-finding test.
Figure 2: Zürich I Prnp−/− mouse behavior resembles that of a known anosmic mouse (Adcy3−/−).
Figure 3: The cookie-finding phenotype is manifest in Prnp knockouts on other genetic backgrounds.
Figure 4: Neuronal PrP expression rescues the cookie-finding phenotype.
Figure 5: Lck-PrP transgenic mice express some neuronal PrPC.
Figure 6: Power of LFPs and duration of the odor response in Prnp−/− mice.
Figure 7: High-frequency oscillations in PrP knockouts are dampened in the course of a single breath.
Figure 8: Paired-pulse synaptic plasticity of field potentials in the GCL after LOT stimulation.

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Acknowledgements

The authors thank members of the Aguzzi laboratory for their assistance, especially G. Miele and P. Schwartz. We also thank J. Manson for the use of the Edinburgh Prnp−/− line, D.-J. Zou and D. Kelley for helpful comments on the behavioral experiments, and J. Gordon for valuable discussions on the electrophysiology data. This work was supported by grants from the National Institute on Deafness and Other Communication Disorders (S.F., C.E.L.P., M.T.V., B.T.S. and A.T.C.). C.E.L.P. also received a Short-Term Fellowship from the European Molecular Biology Organization. A.A. and M.P. were supported by grants from the European Community and the Swiss National Science Foundation.

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Author notes

  1. Magdalini Polymenidou & Botir T Sagdullaev

    Present address: Present addresses: Ludwig Institute for Cancer Research, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA (M.P.) and Weill Medical College of Cornell University, 785 Mamaroneck Avenue, White Plains, New York 10605, USA (B.T.S.).,

Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue, New York, 10027, New York, USA

    Claire E Le Pichon, Matthew T Valley, Alexander T Chesler, Botir T Sagdullaev & Stuart Firestein

  2. Institute of Neuropathology, University Hospital Zürich, Schmelzbergstrasse 12, Zürich, 8091, Switzerland

    Magdalini Polymenidou & Adriano Aguzzi

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Contributions

C.E.L.P., A.T.C., M.P., A.A. and S.F. designed the behavior experiments. M.T.V., B.T.S. and S.F. conceived the electrophysiology experiments. C.E.L.P., A.T.C. and M.P. carried out the cookie-finding behavior experiments and C.E.L.P. and M.T.V. performed the habituation-dishabituation test. C.E.L.P. analyzed all of the behavior experiments and carried out the behavior control experiments. B.T.S. designed the electrophysiology setup. M.T.V. performed the electrophysiology experiments and their analysis. C.E.L.P., M.T.V. and S.F. wrote the paper. All the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Stuart Firestein.

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Le Pichon, C., Valley, M., Polymenidou, M. et al. Olfactory behavior and physiology are disrupted in prion protein knockout mice. Nat Neurosci 12, 60–69 (2009). https://doi.org/10.1038/nn.2238

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