Research reportΔFosB: a molecular switch for long-term adaptation in the brain
Section snippets
Biochemical properties of ΔFosB
The Fos–Jun family of proteins forms the activator protein-1 (AP-1) transcription factor complex that binds AP-1 sites (consensus sequence: TGAC/GTCA) in gene promoters [36]. Genes encoding Fos and Jun family proteins are termed immediate early genes, because they are induced very rapidly in response to a variety of stimuli. This expression is transient, with mRNA and protein levels returning to normal within a few hours.
About 10 years ago, a broad band of Fos-like proteins, originally termed
Induction of ΔFosB in the nervous system
Several types of chronic perturbation have been shown to induce the 35- to 37-kDa isoforms of ΔFosB in the brain, with each type of stimulus showing region-specific patterns of induction (Table 1). Virtually all drugs of abuse induce ΔFosB, including cocaine, opiates, and nicotine, among others [30], [35], [40], [41], [46]. This induction is seen predominantly in the nucleus accumbens and dorsal striatum, although lower levels of induction are seen in several other brain areas, such as
Behavioral plasticity mediated by ΔFosB: role in drug addiction
The first direct evidence for the influence of ΔFosB on complex behavior was obtained from the study of FosB knockout mice [25]. We observed that FosB mutants display a heightened sensitivity to the initial locomotor and rewarding effects of cocaine. However, the mice fail to show behavioral sensitization that normally occurs with repeated drug administration. As well, the FosB mutants show abnormal biochemical, electrophysiological, and behavioral responses to electroconvulsive seizures ([26];
Behavioral plasticity mediated by ΔFosB: role in stress responses
Recent studies have begun to assess the role of ΔFosB in stress responses. While stress induces ΔFosB in several brain regions [45], its induction in nucleus accumbens and dorsal striatum can be best understood within a functional context. Thus, in light of the ability of ΔFosB in striatum to promote aspects of drug addiction, induction of the protein in this region by chronic stress may serve as one mechanism by which stress increases risk for addiction, as seen in many animal models as well
Behavioral plasticity mediated by ΔFosB: role in dyskinesia
Among the stimuli that robustly induce ΔFosB in striatal regions are first-generation antipsychotic drugs, as well as dopamine denervation coupled with repeated dopamine agonist treatment. Induction by chronic administration of antipsychotic drugs is mediated via the D2 antagonist properties of these agents [6], [24], [41]. Induction after dopamine denervation is presumably due to the supersensitivity of dopamine receptors that occurs under these conditions [22]. The functional consequences of
Genomic effects of ΔFosB: overall patterns of gene expression
Because ΔFosB is a transcription factor, it is likely that it produces these complex behavioral phenotypes to drugs of abuse and other stimuli by enhancing or repressing gene expression. As mentioned previously, ΔFosB is a truncated form of FosB that lacks most of the C-terminal transactivation domain of FosB but retains the dimerization and DNA-binding domains. ΔFosB is able to bind to all Jun family members in vitro and binds AP-1 sites in DNA. Although ΔFosB dimerizes predominantly with JunD
Genomic effects of ΔFosB: identification of candidate target genes
Several target genes of ΔFosB have been established using a candidate gene approach (Table 3). One candidate gene is GluR2, an AMPA glutamate receptor subunit [32]. ΔFosB overexpression in inducible bitransgenic mice selectively increases GluR2 expression in the nucleus accumbens, with no effect seen on several other AMPA glutamate receptor subunits analyzed. Conversely, expression of ΔcJun, a dominant negative inhibitor of AP-1 transcription, blocks the ability of cocaine to up-regulate GluR2
Genomic effects of ΔFosB: open-ended search for novel target genes
The second approach that has been used to identify target genes of ΔFosB has measured the gene expression changes that occur upon ΔFosB (or ΔcJun) expression using DNA microarrays, as described earlier. Studies using the bitransgenic mice that overexpress ΔFosB specifically in the striatum after doxycycline removal have led to the identification of many genes that are up- or down-regulated by ΔFosB expression [4], [18], [19], [34]. Two genes which appear to be induced through ΔFosB's actions as
Future directions
Increasing evidence supports the view that ΔFosB is a unique transcription factor based on its induction in brain by a range of chronic perturbations and on its high level of stability. There is also growing evidence for an important role of ΔFosB in animal models of drug addiction, Parkinson's disease, and depression and antidepressant action. Using both candidate gene and open-ended DNA microarray approaches, numerous putative targets for ΔFosB have been identified in brain, and in some cases
Acknowledgements
This work was supported by grants from the National Institute on Drug Abuse and National Institute of Mental Health.
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