BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments - PubMed (original) (raw)

. 2008 Jun 24;105(25):8766-71.

doi: 10.1073/pnas.0803736105. Epub 2008 Jun 18.

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

Affiliations

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

Sungho Maeng et al. Proc Natl Acad Sci U S A. 2008.

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, glucocorticoids 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+/- 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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Increased activity of BAG1 TG mice in the open arms of elevated plus maze (EPM). EPM was performed under ambient light (20 lux) as detailed in

SI Methods

. The time spent in open arms (A) and the ratio of travel distance (open/total arms) for 5 min (B) were plotted. Data represent mean ± SEM (n = 12 mice per group); *, P < 0.05, Student's t test.

Fig. 2.

Fig. 2.

Facilitated spontaneous recovery of BAG1 TG mice in learned-helplessness paradigm. (A) Forced swim test in BAG1 TG mice. No significant genotype difference in immobility times was detected. (B) Learned-helplessness paradigm. No genotype difference was detected in the number of BAG1 TG versus WT mice that became helpless. (C) BAG1 TG helpless mice were assessed again on days 2 and 8. Significantly fewer helpless mice were found in the BAG1 TG mouse group. (D) There was a smaller percentage of recovered-helplessness mice in the BAG1+/− mice group. However, no significant differences between BAG1+/− and C57BL/6J WT mice were detected on number of escape failures. (E) Shortened escape latencies were found in the BAG1 TG mouse group. (F) No significant differences were found in escape latencies between BAG1+/− and WT mice at assessment days 1, 3, 7, and 12. For BAG1 TG vs. WT mice, data represent mean ± SEM (n = 6∼13 mice per group); *, P < 0.05; **, P < 0.01, compared with WT on the same day, two-way ANOVA, Tukey's post hoc test.

Fig. 3.

Fig. 3.

Accelerated recovery and sensitization resilience of BAG1 TG mice in psychostimulant models of mania: amphetamine. (A–D) Amphetamine-induced hyperlocomotion. Locomotor activities were monitored for 2 h before (A) and after (C) 2 mg/kg amphetamine, and for 6 h before (B) and after (D) 5 mg/kg amphetamine injection. In the experiments with 2 mg/kg amphetamine, locomotor activity was reduced to baseline levels within 2 h, and there was no significant genotype difference (C). In the experiments with 5 mg/kg amphetamine, BAG1 TG mice showed facilitated reduction in locomotion (D), and genotype differences were significant.

Fig. 4.

Fig. 4.

Blunted response of BAG1 TG mice but increased sensitization of BAG1+/− mice in the cocaine-induced behavioral sensitization mode of mania. Locomotor activity was monitored after repeated injections of saline [for BAG1 TG mice (A) and for BAG1+/− (B)] or cocaine [20 mg/kg i.p. for BAG1 TG (C); 10 mg/kg i.p. for BAG1+/− mice (D)] for 5 consecutive days. A challenge test with the same dose of cocaine was performed 1 week after the last cocaine injection. Repeated injections with cocaine, but not saline, caused gradual locomotion increases in WT, BAG1 TG mice and BAG1+/− mice (A–D). The repeated cocaine injection-induced locomotion increases were significantly less in BAG1 TG mice than FVB/n WT mice (C) (n = 8–12 mice per group; *, P < 0.05; **, P < 0.01 compared with WT at the same time block, two-way ANOVA, Tukey's post hoc test). The repeated cocaine injection-induced locomotion increases were significantly greater in BAG1+/− mice than C57BL/6J mice (D) [F (1, 56) = 6.924, P = 0.0110]. Data represent mean ± SEM.

Fig. 5.

Fig. 5.

Neurochemical changes induced by BAG1 overexpression. Significant genotype effects were observed in levels of Hsp70 (B) and FKBP51 (C), but not GR (A), Bcl-2 (D), or ERK (E). Data represent mean ± SEM of percentage change compared with WT mice; *, P < 0.05, Student's t test.

Comment in

Similar articles

Cited by

References

    1. Belmaker RH. Bipolar disorder. N Engl J Med. 2004;351:476–486. - PubMed
    1. Fagiolini A, et al. Functional impairment in the remission phase of bipolar disorder. Bipolar Disord. 2005;7:281–285. - PubMed
    1. Revicki DA, Matza LS, Flood E, Lloyd A. Bipolar disorder and health-related quality of life: Review of burden of disease and clinical trials. Pharmacoeconomics. 2005;23:583–594. - PubMed
    1. Tohen M, et al. The McLean–Harvard First-Episode Mania Study: Prediction of recovery and first recurrence. Am J Psychiatry. 2003;160:2099–2107. - PubMed
    1. Kupfer DJ. The increasing medical burden in bipolar disorder. J Am Med Assoc. 2005;293:2528–2530. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources