The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers

Abstract

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.

Expression profile of Bag 1 in the postmortem brain

“…Hippocampal homogenates collected from rats immediately after death (i.e., absolute control animals) showed a distinctive band with a MW of ∼32 kDa. This isoform corresponds well with one of the three bands identified in rodent tissue (Zhou et al, 2005). An identical band of ∼32 kDa was also detected in the hippocampus of postmortem rats maintained at either 24 °C or 4 °C storage temperatures.…”

“…Whether increases in Bag 1 activity can also be traced to changes in temperature in vivo is not known. The observation that administration of lithium and valproate increases the expression of Bag 1 by inhibiting the glucocorticoid receptor in the rat hippocampus (Zhou et al, 2005), raises the possibility that hypothermia might be an additional factor in modulating the activity of Bag 1. Schematic diagram of the experimental steps instituted for studying postmortem variables and Bag 1 expression.…”

“…Against this background, we examined the expression profile and cellular stability of Bag 1 in rat brains collected after a 4 hr postmortem interval. There is currently much interest in the involvement of Bag 1 expression in psychiatry as this protein is a long-term target for the actions of mood stabilizers (e.g., lithium and valproate) in bipolar depression (Zhou et al, 2005). Accordingly, it would be valuable to determine potential confounding effects of postmortem factors on Bag 1 immunoreactivity (IR), especially if autopsy-derived human specimens are to be used in psychiatric studies of disease pathophysiology and drug therapy.…”

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…169,170 In addition to lithium's effects on a number of intracellular cascades, lithium also induces the expression of BDNF and subsequent activation of TrkB, the receptor for BDNF, in cortical neurons. The activation of BDNF/TrkB signaling is essential for the neuroprotective effects of this drug.…”

Reverse translational strategies for developing animal models of bipolar disorder

“…Interest in BAG-1 as a putative mediator of affective resilience initially arose out of microarray studies which demonstrated that two agents that are structurally highly dissimilar -lithium and valproate -increased levels of BAG-1 mRNA, protein and function (Zhou et al, 2005). BAG-1 exerts three functions that make it potentially noteworthy in the pathophysiology and treatment of BD:…”