한빛사논문
- 조회2,606
Abstract
![{dagger}](\"http://www.pnas.org/math/dagger.gif\")
,![{ddagger}](\"http://www.pnas.org/math/link//Dagger.gif\")
, John C. Reed![](\"http://www.pnas.org/math/sect.gif\")
, and Husseini K.
Manji*,¶
*Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood
and Anxiety Disorders Program, National Institute of Mental Health, National
Institutes of Health, Department of Health and Human Services, Bethesda, MD
20892; Laboratory
of Neuroendocrinology, The Rockefeller University, New York, NY 10021; and
Burnham Institute for
Medical Research, La Jolla, CA 92037
Contributed by Bruce McEwen, April 17, 2008 (sent for review October 11, 2007)
Abstract
Recent microarray studies with stringent validating criteria identified Bcl-2-associated athanogene (BAG1) as a target for the actions of medications that are mainstays in the treatment of bipolar disorder (BPD). BAG1 is a Hsp70/Hsc70-regulating cochaperone that also interacts with glucocorticoid receptors (GRs) and attenuates their nuclear trafficking and function. Notably, glucocorticoids are one of the few agents capable of triggering both depressive and manic episodes in patients with BPD. As a nexus for the actions of glucocorticoids and bipolar medications, we hypothesized that the level of BAG1 expression would play a pivotal role in regulating affective-like behaviors. This hypothesis was investigated in neuron-selective BAG1 transgenic (TG) mice and BAG1 heterozygous knockout (+/-) mice. On mania-related tests, BAG1 TG mice recovered much faster than wild-type (WT) mice in the amphetamine-induced hyperlocomotion test and displayed a clear resistance to cocaine-induced behavioral sensitization. In contrast, BAG1+/- mice displayed an enhanced response to cocaine-induced behavioral sensitization. The BAG1 TG mice showed less anxious-like behavior on the elevated plus maze test and had higher spontaneous recovery rates from helplessness behavior compared with WT mice. In contrast, fewer BAG1+/- mice recovered from helplessness behavior compared with their WT controls. BAG1 TG mice also exhibited specific alterations of hippocampal proteins known to regulate GR function, including Hsp70 and FKBP51. These data suggest that BAG1 plays a key role in affective resilience and in regulating recovery from both manic-like and depression-like behavioral impairments.
FKBP51 | lithium | valproate | mood disorders | resilience
Footnotes
Author contributions: S.M., J.G.H., R.Z., J.D., G.C., and H.K.M. designed research; S.M., J.G.H., B.P., P.Y., Y. Wang, Y. Wei, J.M., and R.J.S. performed research; B.M. and J.C.R. contributed new reagents/analytic tools; S.M., J.G.H., G.C., B.M., J.C.R., and H.K.M. analyzed data; and S.M., J.G.H., G.C., B.M., J.C.R., and H.K.M. wrote the paper.
The authors declare no conflict of interest.
![{ddagger}](\"http://www.pnas.org/math/Dagger.gif\")
To whom correspondence may be addressed.
¶To whom correspondence may be addressed at: Mood and Anxi...
논문정보
- Research article
- 2008년 06월 (BRIC 등록일 )
- 국외 연구진
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