Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of [Delta]FosB.
The transcription factor DeltaFosB is induced in the hippocampus and other brain regions by repeated electroconvulsive seizures (ECS), an effective antidepressant treatment. The unusually high stability of this protein makes it an attractive candidate to mediate some of the long-lasting changes in the brain caused by ECS treatment. To understand how DeltaFosB might alter brain function, we examined the gene expression profiles in the hippocampus of inducible transgenic mice that express DeltaFosB in this brain region by the use of cDNA expression arrays that contain 588 genes. Of the 430 genes detected, 20 genes were consistently upregulated, and 14 genes were downregulated, by >50%. One of the upregulated genes is cyclin-dependent kinase 5 (cdk5). On the basis of its purported role in regulating neuronal structure, we studied directly whether cdk5 is a true target for DeltaFosB. Upregulation of cdk5 immunoreactivity in the hippocampus was confirmed by Western blotting in the DeltaFosB-expressing transgenic mice as well as in rats treated chronically with ECS. Chronic ECS treatment also increased, in the hippocampus, the phosphorylation state of tau, a microtubule-associated protein that is a known substrate for cdk5. A 1.6 kb fragment of the cdk5 promoter was cloned, and activity of the promoter was found to be increased after overexpression of DeltaFosB in cell culture. Moreover, mutation of the single consensus activator protein-1 site contained within the cdk5 promoter fragment completely abolished activation of the promoter by DeltaFosB. Together, these results suggest that cdk5 is one target by which DeltaFosB produces some of its physiological effects in the hippocampus and thereby mediates certain long-term consequences of chronic ECS treatment.
Chen
J
J
Laboratory of Molecular Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.
Zhang
Y
Y
Kelz
M B
MB
Steffen
C
C
Ang
E S
ES
Zeng
L
L
Nestler
E J
EJ
D000818:Animals; D015153:Blotting, Western; D002384:Catalysis; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004597:Electroshock; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012045:Regulatory Sequences, Nucleic Acid; D012640:Seizures / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases