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The Journal of Neuroscience, May 4, 2005, 25(18):4493-4502; doi:10.1523/JNEUROSCI.4530-04.2005
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Cellular/Molecular
The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers
Rulun Zhou,1,3 Neil A. Gray,1,4 Peixiong Yuan,1 Xiaoxia Li,3 Jingshan Chen,2 Guang Chen,1 Patricia Damschroder-Williams,1 Jing Du,1 Lei Zhang,1,3 andHusseini K. Manji1,4 1Laboratory of Molecular Pathophysiology and 2Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, Maryland 20852, 3Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, and 4College of Physicians and Surgeons, Columbia University, New York, New York 10032
Increasing data suggest that impairments of cellular plasticity/resilience underlie the pathophysiology of bipolar disorder. A series of microarray studies with validating criteria have recently revealed a common, novel target for the long-term actions of the structurally highly dissimilar mood stabilizers lithium and valproate: BAG-1 [BCL-2 (B-cell CLL/lymphoma 2)-associated athanogene]. Because BAG-1 attenuates glucocorticoid receptor (GR) nuclear translocation, activates ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases, and potentiates anti-apoptotic functions of BCL-2, extensive additional studies were undertaken. Chronic administration of both agents at therapeutic doses increased the expression of BAG-1 in rat hippocampus. Furthermore, these findings were validated at the protein level, and the effects were seen in a time frame consistent with therapeutic effects and were specific for mood stabilizers. Functional studies showed that either lithium or valproate, at therapeutically relevant levels, inhibited dexamethasone-induced GR nuclear translocation and inhibited GR transcriptional activity. Furthermore, small interfering RNA studies showed that these inhibitory effects on GR activity were mediated, at least in part, through BAG-1. The observation that BAG-1 inhibits glucocorticoid activation suggests that mood stabilizers may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder by upregulating BAG-1. Additionally, these studies suggest that regulation of GR-mediated plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents affecting BAG-1 more directly may represent novel therapies for this devastating illness.
Key words: lithium; valproate; bipolar disorder; BAG-1; glucocorticoid; neuroplasticity
Received Nov 4, 2004; revised March 28, 2005; accepted March 28, 2005.
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