BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments

Sungho Maeng, Joshua G. Hunsberger, Brandon Pearson, Peixiong Yuan, Yun Wang, Yanling Wei, Joseph McCammon, Robert J. Schloesser, Rulun Zhou, Jing Du, Guang Chen, Bruce McEwen, John C. Reed, Husseini K. Manji

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

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, glu-cocorticoids 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 + I - 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.

Original languageEnglish
Pages (from-to)8766-8771
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number25
DOIs
Publication statusPublished - 24 Jun 2008

Keywords

  • FKBP51
  • Lithium
  • Mood disorders
  • Resilience
  • Valproate

Fingerprint

Dive into the research topics of 'BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments'. Together they form a unique fingerprint.

Cite this