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The Journal of Neuroscience, December 15, 2000, 20(24):8965-8971

Induction of Cyclin-Dependent Kinase 5 in the Hippocampus by Chronic Electroconvulsive Seizures: Role of FosB

Jingshan Chen, Yajun Zhang, Max B. Kelz, Cathy Steffen, Eugenius S. Ang, Ling Zeng, and Eric J. Nestler

Laboratory of Molecular Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508

The transcription factor FosB 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 FosB might alter brain function, we examined the gene expression profiles in the hippocampus of inducible transgenic mice that express FosB 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 FosB. Upregulation of cdk5 immunoreactivity in the hippocampus was confirmed by Western blotting in the FosB-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 FosB 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 FosB. Together, these results suggest that cdk5 is one target by which FosB produces some of its physiological effects in the hippocampus and thereby mediates certain long-term consequences of chronic ECS treatment.

Key words: cdk5; FosB; hippocampus; electroconvulsive seizures; transcription factors; antidepressant treatments; inducible transgenic mice; gene expression

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20248965-07$05.00/0

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