Article abstract

Nature Neuroscience 10, 1012 - 1019 (2007)
Published online: 15 July 2007 | doi:10.1038/nn1943

A hippocampal Cdk5 pathway regulates extinction of contextual fear

Farahnaz Sananbenesi1,2, Andre Fischer1,2, Xinyu Wang1, Christina Schrick3, Rachael Neve4, Jelena Radulovic3 & Li-Huei Tsai1

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.

  1. Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
  2. European Neuroscience Institute (ENI), Grisebach Str. 5, Medical School University Goettingen, Max Planck Society, Göttingen, 37077, Germany.
  3. Department of Psychiatry and Behavioral Sciences, 20 East Superior Street, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
  4. Molecular Neurogenetics, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA.

Correspondence to: Li-Huei Tsai1 e-mail:

Correspondence to: Jelena Radulovic3 e-mail:

Correspondence to: Andre Fischer1,2 e-mail:


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