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

Chen, Jingshan; Zhang, Yajun; Kelz, Max B.; Steffen, Cathy; Ang, Eugenius S. B. C.; Zeng, Le; Nestler, Eric J.

doi:10.1523/jneurosci.20-24-08965.2000

Cited by 104 publications

(102 citation statements)

References 38 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…This approach has led to the identification of many genes that are up-or downregulated by DFosB expression in this brain region (Chen et al 2000(Chen et al , 2003Ang et al 2001;McClung & Nestler 2003). Two genes that appear to be induced through DFosB's actions as a transcriptional activator are cyclin-dependent kinase-5 (Cdk5) and its cofactor P35 (Bibb et al 2001;McClung & Nestler 2003).…”

Section: Target Genes For Dfosb In Nucleus Accumbensmentioning

confidence: 99%

“…Two genes that appear to be induced through DFosB's actions as a transcriptional activator are cyclin-dependent kinase-5 (Cdk5) and its cofactor P35 (Bibb et al 2001;McClung & Nestler 2003). Cdk5 is also induced by chronic cocaine in the nucleus accumbens, an effect blocked upon DcJun expression, and DFosB binds to and activates the Cdk5 gene through an AP-1 site in its promoter (Chen et al 2000;Peakman et al 2003). Cdk5 is an important target of DFosB since its expression has been directly linked to changes in the phosphorylation state of numerous synaptic proteins including glutamate receptor subunits (Bibb et al 2001), as well as increases in dendritic spine density (Norrholm et al 2003;Lee et al 2006), in the nucleus accumbens, which are associated with chronic cocaine administration (Robinson & Kolb 2004).…”

Section: Target Genes For Dfosb In Nucleus Accumbensmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional mechanisms of addiction: role of ΔFosB

Nestler

2008

Phil. Trans. R. Soc. B

347

381

View full text Add to dashboard Cite

Regulation of gene expression is considered a plausible mechanism of drug addiction, given the stability of behavioural abnormalities that define an addicted state. Among many transcription factors known to influence the addiction process, one of the best characterized is DFosB, which is induced in the brain's reward regions by chronic exposure to virtually all drugs of abuse and mediates sensitized responses to drug exposure. Since DFosB is a highly stable protein, it represents a mechanism by which drugs produce lasting changes in gene expression long after the cessation of drug use. Studies are underway to explore the detailed molecular mechanisms by which DFosB regulates target genes and produces its behavioural effects. We are approaching this question using DNA expression arrays coupled with the analysis of chromatin remodelling-changes in the posttranslational modifications of histones at drug-regulated gene promoters-to identify genes that are regulated by drugs of abuse via the induction of DFosB and to gain insight into the detailed molecular mechanisms involved. Our findings establish chromatin remodelling as an important regulatory mechanism underlying drug-induced behavioural plasticity, and promise to reveal fundamentally new insight into how DFosB contributes to addiction by regulating the expression of specific target genes in brain reward pathways.

show abstract

Section: Target Genes For Dfosb In Nucleus Accumbensmentioning

confidence: 99%

Section: Target Genes For Dfosb In Nucleus Accumbensmentioning

confidence: 99%

Transcriptional mechanisms of addiction: role of ΔFosB

Nestler

2008

Phil. Trans. R. Soc. B

347

381

View full text Add to dashboard Cite

show abstract

“…Therefore, identification of the target genes that are regulated by ⌬FosB induction is expected to contribute to a greater understanding of the molecular mechanism underlying cocaine addiction. Recently, chronic treatment of animals with cocaine has been shown to up-regulate the expression of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in the striatum through the induction of ⌬FosB (6,7).…”

mentioning

confidence: 99%

Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Takahashi

Ohshima

Cho

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cocaine, a drug of abuse, increases synaptic dopamine levels in the striatum by blocking dopamine reuptake at axon terminals. Cyclindependent kinase 5 (Cdk5) and its activator p35, proteins involved in phosphorylation of substrates in postmitotic neurons, have been found to be up-regulated after chronic exposure to cocaine. To further examine the effects of Cdk5 and p35 induction on striatal dopamine signaling, we generated two independent transgenic mouse lines in which Cdk5 or p35 was overexpressed specifically in neurons. We report here that increased Cdk5 activity, as a result of p35 but not of Cdk5 overexpression, leads to attenuation of cocaine-mediated dopamine signaling. Increased Cdk5-mediated phosphorylation of dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa (DARPP-32) at Thr-75, was accompanied by decreased phosphorylation of DARPP-32 at Thr-34. Increased Cdk5-mediated phosphorylation of extracellular signalregulated kinase kinase 1 at Thr-286 was accompanied by decreased activation of extracellular signal-regulated kinase 1͞2. These effects contributed to attenuation of cocaine-induced phosphorylation of cAMP response element-binding protein as well as a lesser induction of c-fos in the striatum. These results support the idea that Cdk5 activity is involved in altered gene expression after chronic exposure to cocaine and hence impacts the long-lasting changes in neuronal function underlying cocaine addiction.cocaine addiction ͉ phosphorylation ͉ striatum C ocaine increases synaptic dopamine levels in the striatum and alters gene expression in the dopaminoceptive neurons by activating intracellular pathways that propagate the initial signal from the dopamine D1 receptor to the nucleus (1). Chronic exposure to cocaine up-regulates several transcription factors, resulting in the long-lasting changes in gene expression that are thought to underlie neuronal adaptations in cocaine addiction (2). ⌬FosB, identified as such a transcription factor (3), has been shown to enhance the behavioral responsiveness of animals to cocaine (4, 5). Therefore, identification of the target genes that are regulated by ⌬FosB induction is expected to contribute to a greater understanding of the molecular mechanism underlying cocaine addiction. Recently, chronic treatment of animals with cocaine has been shown to up-regulate the expression of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in the striatum through the induction of ⌬FosB (6, 7).Cdk5 is a member of the Cdk family of serine͞threonine kinases. Unlike other Cdks that are major regulators of cell-cycle progression, Cdk5 is mainly involved in phosphorylation of substrates in postmitotic neurons (8). The neuronal specificity of Cdk5 activity is achieved through the association with its activators, either p35 or p39, which are predominantly expressed in postmitotic neurons (8). In addition to the essential role of Cdk5 in brain development (9, 10), it has also been implicated in dopaminergic transmission in postnatal brain (11,12). Inhibition of ...

show abstract

“…DFosB is an alternatively spliced variant of the fosB gene. Like c-Fos, DFosB forms heterodimers with Jun proteins, mainly JunD, to form active activator protein-1 (AP-1) complexes, which then bind to AP-1 sites in the promoter regions of many neural genes (Chen et al, 2000). DFosB lacks a portion of the C-terminus, which is the major transactivation domain of full-length FosB (Nakabeppu et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, DFosB may be a weak transcriptional activator and in some cases may function as a transcriptional repressor (Nakabeppu and Nathans, 1991). Several downstream target genes for DFosB have been identified to date, including NMDAR1, GluR2, cyclin-dependent kinase-5 (Cdk5), and NF-kB (Hiroi et al, 1998;Kelz et al, 1999;Chen et al, 2000;Ang et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the CCAAT-Enhancer Binding Protein β in ΔFosB Transgenic Mice and by Electroconvulsive Seizures

Chen

Newton

Zeng

et al. 2003

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Previous studies demonstrate that chronic, but not acute electroconvulsive seizures (ECS), increases levels of DFosB, a long-lasting transcription factor, in the hippocampus, and this effect correlates with the slow onset and long-lasting clinical effects of antidepressant treatment. To understand how DFosB mediates long-term plasticity in the hippocampus, we analyzed the gene expression profile of inducible transgenic mice expressing DFosB with a highly sensitive microarray assay and a customized computer analysis program. The CCAAT-enhancing binding protein-b (C/EBPb) was identified as one of the genes downregulated by DFosB in the hippocampus. The downregulation of C/EBPb in the inducible DFosB transgenic mice was confirmed by other quantitative assays including real-time RT-PCR and low density dot blotting. Analysis of the C/EBPb expression in the hippocampus of rats treated with ECS revealed that the C/EBPb mRNA was also downregulated by chronic, but not acute ECS administration, the most effective treatment for depression. Given the reported role of C/EBPb in behavioral conditioning models, it is possible that the DFosB-mediated downregulation of C/EBPb in the hippocampus may be a molecular mechanism by which antidepressants alleviate some of the symptoms of depressed patients.

show abstract

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

Cited by 104 publications

References 38 publications

Transcriptional mechanisms of addiction: role of ΔFosB

Transcriptional mechanisms of addiction: role of ΔFosB

Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Downregulation of the CCAAT-Enhancer Binding Protein β in ΔFosB Transgenic Mice and by Electroconvulsive Seizures

Contact Info

Product

Resources

About