Cyclin-dependent kinase 5 is required for associative learning.
Transient stressful experiences may persistently facilitate associative and nonassociative learning, possibly through alterations of gene expression. Here we identify, by subtractive hybridization, differential expression of the Cdk5 gene in response to stress. The Cdk5 protein is selectively induced in the fibers of septohippocampal cholinergic neurons but not in other regions of prominent Cdk5 production. This upregulation is accompanied by increased Cdk5 kinase activity, which is blocked completely by the Cdk5 inhibitor butyrolactone I. Microinjection of butyrolactone I into the lateral septum and hippocampus prevents the acquisition of conditioned context-dependent fear as well as its stress-induced facilitation. By demonstrating that a transient increase of Cdk5 activity within the septohippocampal system is required for associative learning, an important novel role of Cdk5 has been identified.
Fischer
André
A
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany. fischer@mail.em.mpg.de
Sananbenesi
Farahnaz
F
Schrick
Christina
C
Spiess
Joachim
J
Radulovic
Jelena
J
D015107:4-Butyrolactone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D001245:Association Learning / Q000502:physiology*; D002799:Cholinergic Fibers / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005080:Exercise Test; D005239:Fear / Q000502:physiology; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008845:Microinjections; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020665:Septum of Brain / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C082868:butyrolactone I; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D015107:4-Butyrolactone