FosB Is Essential for the Enhancement of Stress Tolerance and Antagonizes Locomotor Sensitization by ΔFosB

Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
Biological psychiatry (Impact Factor: 10.26). 06/2011; 70(5):487-95. DOI: 10.1016/j.biopsych.2011.04.021
Source: PubMed


Molecular mechanisms underlying stress tolerance and vulnerability are incompletely understood. The fosB gene is an attractive candidate for regulating stress responses, because ΔFosB, an alternative splice product of the fosB gene, accumulates after repeated stress or antidepressant treatments. On the other hand, FosB, the other alternative splice product of the fosB gene, expresses more transiently than ΔFosB but exerts higher transcriptional activity. However, the functional differences of these two fosB products remain unclear.
We established various mouse lines carrying three different types of fosB allele, wild-type (fosB(+)), fosB-null (fosB(G)), and fosB(d) allele, which encodes ΔFosB but not FosB, and analyzed them in stress-related behavioral tests.
Because fosB(+/d) mice show enhanced ΔFosB levels in the presence of FosB and fosB(d/d) mice show more enhanced ΔFosB levels in the absence of FosB, the function of FosB can be inferred from differences observed between these lines. The fosB(+/d) and fosB(d/d) mice showed increased locomotor activity and elevated Akt phosphorylation, whereas only fosB(+/d) mice showed antidepressive-like behaviors and increased E-cadherin expression in striatum compared with wild-type mice. In contrast, fosB-null mice showed increased depression-like behavior and lower E-cadherin expression.
These findings indicate that FosB is essential for stress tolerance mediated by ΔFosB. These data suggest that fosB gene products have a potential to regulate mood disorder-related behaviors.

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Available from: Yusaku Nakabeppu
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    • "To date, functions of Fosb gene products in brain have been characterized almost exclusively in neurons, because neurons uniquely express high levels of Fosb products in response to several brain stimuli (Hope et al., 1994; Mandelzys et al., 1997; McClung et al., 2004; Kurushima et al., 2005; Nestler, 2008; Ohnishi et al., 2011). In the present study, we revealed for the first time that the Fosb gene is also expressed in microglia as well as neurons in the brain, and regulates different target genes in each type of brain cell. "
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    • "As a consequence, DeltaFosB have been viewed as a sustained molecular switch to mediate forms of long-lasting neural and behavioral plasticity. Interestingly, an elegant study using mouse lines expressing differentially FosB and DeltaFosB showed that FosB is essential for the enhancement of stress tolerance and also neutralizes the correlation between psychostimulant-induced locomotor sensitization and accumulation of DeltaFosB in the striatum (Ohnishi et al., 2011). Therefore, both proteins could play important roles in the experimental protocol used in the present study. "
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