Bipolar Disorder (BD) is a common severe, chronic, and life-threatening illness; despite much research, however, there is a dearth of knowledge concerning the underlying molecular neurobiology. It has become increasingly appreciated in recent years that the long term treatment of mood disorders likely involves the strategic regulation of signaling pathways and gene expression in critical neuronal circuits While advances in microarray methodologies have greatly enhanced our ability to identify novel targets, a major problem inherent in neuropharmacologic research is the attribution of therapeutic relevance to any observed biochemical target. We have therefore implemented a series of validating criteria, including the following: (1) dose and time frame consistent with clinical therapeutic effects; (2) observed with structurally highly dissimilar but clinically efficacious agents; (3) specific to brain regions implicated in the disorder (4) specific for mood stabilizers (5) validated at a protein level. Using these stringent criteria, our recent microarray studies have revealed a novel target for the long-term actions of the mood stabilizers lithium and valproate. Chronic administration of both agents at therapeutic doses increased the expression of BAG-1 (bcl-2 associated athanogene) in the hippocampus. Furthermore, these findings were validated at the protein level, and were confirmed in human neuroblastoma cells using similar stringent criteria. Bag-1 is an important chaperone of bcl-2, and enhances bcl-2!|s anti-apoptotic functions; furthermore, through interaction with raf, Bag-1 is able to activate ERK MAP kinases. Consistent with this, we found that lithium and valproate activate ERK MAP kinases and exert anti-apoptotic effects. Bag-1 also inhibits glucocorticoid activation, which may counteract the deleterious effects of hypercortisolemia seen in BD. SH-SY5Y cells were therefore co-transfected with glucocorticoid response element (GRE) and glucocorticoid receptor alpha (GR??) and functional studies were undertaken. We found that chronic lithium (at therapeutic concentrations) inhibits glucocorticoid activation. The time frame and the effective drug concentrations show the same pattern as that induced up-regulated bag-1. Together, the data suggests that Bag-1 may represent a novel, highly therapeutically relevant target in the long-term treatment of bipolar disorder.
