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A hippocampal Cdk5 pathway regulates extinction of contextual fear

Nature Neuroscience volume 10, pages 1012–1019 (2007)Cite this article

Abstract

Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.

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Figure 1: Inhibition of hippocampal Cdk5 activity facilitates extinction.
Figure 2: Increased Cdk5 activity in CK-p25 Tg mice impairs extinction.
Figure 3: Membrane association of Cdk5 and p35 during extinction is regulated by Rac-1.
Figure 4: Inhibition of Rac-1 facilitates extinction.
Figure 5: Cdk5 affects PAK-1 activity during extinction.
Figure 6: PAK-1 activity promotes extinction.

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Acknowledgements

We thank B. Samuels for reading the manuscript and for critical discussion, all members of the Tsai lab for helpful advice, M. Nikolic for the pPAK-1T212 antibody and S. Tonegawa for the dominant-negative PAK-1 construct. L.-H.T. is an investigator of the Howard Hughes Medical Institute. This work was partially supported by a US National Institutes of Health grant (NS051874) to L.-H.T. This work was also partially supported by a US National Institute of Mental Health grant MH073669 to J.R., and a Humboldt/Deutsche Forschungsgemeinschaft fellowship to F.S. and A.F., respectively, and by funds from the European Neuroscience Institute Goettingen to A.F. The European Neuroscience Institute is jointly funded by the Medical School University Goettingen and the Max Planck Society.

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Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Farahnaz Sananbenesi, Andre Fischer, Xinyu Wang & Li-Huei Tsai

  2. European Neuroscience Institute (ENI), Grisebach Str. 5, Medical School University Goettingen, Max Planck Society, Göttingen, 37077, Germany

    Farahnaz Sananbenesi & Andre Fischer

  3. Department of Psychiatry and Behavioral Sciences, 20 East Superior Street, Northwestern University, Feinberg School of Medicine, Chicago, 60611, Illinois, USA

    Christina Schrick & Jelena Radulovic

  4. Molecular Neurogenetics, McLean Hospital, 115 Mill Street, Belmont, 02478, Massachusetts, USA

    Rachael Neve

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Contributions

The studies were conceived and designed by F.S., A.F., J.R. and L.-H.T. F.S., A.F., X.W., C.S., R.N. and J.R. contributed to the experiments in this work. The paper was written by A.F. and L.-H.T.

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Correspondence to Andre Fischer, Jelena Radulovic or Li-Huei Tsai.

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Sananbenesi, F., Fischer, A., Wang, X. et al. A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci 10, 1012–1019 (2007). https://doi.org/10.1038/nn1943

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