The mood stabilizers lithium and valproate are both effective in the treatment of bipolar disorder; however, their therapeutic mechanisms remain unclear. Because of the delayed onset of clinical efficacy (days to weeks), it has been proposed that adaptive changes in gene expression, rather than initial pharmacological actions, may be directly responsible. Using cDNA microarray as the initial screening method, we discovered that chronic administration of both agents at therapeutic doses increased the expression of BAG-1 (bcl-2 associated athanogene) in rat hippocampus. Furthermore, these findings were validated in the hippocampus at the protein level, the effects were seen in a time frame consistent with therapeutic effects, and were specific for mood stabilizers. BAG -1 is an important chaperone of bcl-2 (B-cell CLL/lymphoma 2), and enhances bcl-2?s anti-apoptotic functions; furthermore, through interaction with raf (v-raf-1 murine leukemia viral oncogene homolog 1), BAG-1 is able to activate ERK (extracellular signal-regulated protein kinase) MAP (mitogen-activated protein) kinases. Consistent with this, we previously found that lithium and valproate activate ERK MAP kinases. Bag-1 also inhibits GR (glucocorticoid receptor) activation, which may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder. Anti-GR antibody immunostaining plus double staining with DAPI (4',6-Diamidino-2-phenylindole) showed either lithium or VPA, at therapeutically relevant levels, inhibited dexamethasone induced GR nuclear translocation. In addition, glucocorticoid response element (GRE) transfection assay showed lithium, at therapeutically relevant levels, inhibited GR activity in cultured human cells. Evaluated through siRNA (short interference RNA) silencing of BAG-1, the inhibition of mood stabilizers to GR nuclear translocation and to GR activity is mediated, at least in part, by BAG-1. The effect that BAG-1 inhibits glucocorticoid activation suggests mood stabilizers may counteract the deleterious effects of hypercortisolemia seen in bipolar disorder by up-regulating BAG-1. The role of BAG-1 in behavioral plasticity relevant to mood disorders was further investigated in wild-type and BAG-1 transgenic mice using a battery of behavioral tests. Initial findings suggest BAG-1 transgenic mice display a behavioral resilience phenotype. The mice showed less anxiety-related and more exploration-type activities in the elevated plus maze test. Three tests for depression-like behavior were conducted. The transgenic mice performed similarly to wild type mice on the forced swim test and the tail suspension test. However, transgenic mice were rapidly recovered from helplessness on a more stressful test, the learned helplessness paradigm. Two mania-related tests were also performed. The mice showed more locomotion stability in the amphetamine challenge test and more resistant in cocaine induced behavioral sensitization test. The behavioral phenotype of BAG1 transgenice mice is also associated with hippocampal alterations of stress-related proteins including Hsp70, GR and FKBP51. Together, the data suggests that BAG-1 may represent a novel, highly therapeutically relevant target in the long-term treatment of bipolar disorder and play role in mood stability.
