A hippocampal Cdk5 pathway regulates extinction of contextual fear.
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.
Sananbenesi
Farahnaz
F
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.
Fischer
Andre
A
Wang
Xinyu
X
Schrick
Christina
C
Neve
Rachael
R
Radulovic
Jelena
J
Tsai
Li-Huei
LH
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D003214:Conditioning, Classical / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D047428:Protein Kinase Inhibitors; C082868:butyrolactone I; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D015107:4-Butyrolactone