A hippocampal Cdk5 pathway regulates extinction of contextual fear
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Tsai_A Hippocampal cdk5.pdf
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1.59 MB
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Author(s)
Sananbenesi, Farahnaz
Fischer, Andre
Wang, Xinyu
Schrick, Christina
Neve, Rachael L.
Radulovic, Jelena
Tsai, Li-Huei
Date Issued
July 2007
Journal
Nature Neuroscience
Publisher
Nature Publishing Group
Citation
Sananbenesi, Farahnaz et al. “A Hippocampal Cdk5 Pathway Regulates Extinction of Contextual Fear.” Nature Neuroscience 10.8 (2007): 1012–1019.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/nn1943
