The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure

Several intracellular pathways that contribute to the adaptation or maladaptation to environmental challenges mediate the vulnerability and resilience to chronic stress. The activity of the hypothalamic-pituitary-adrenal (HPA) axis is fundamental for the proper maintenance of brain processes, and it is related to the functionality of the isoform alfa and beta of the glucocorticoid receptor (Gr), the primary regulator of HPA axis. Among the downstream effectors of the axis, the scaffolding protein RACK1 covers an important role in regulating synaptic activity and mediates the transcription of the neurotrophin Bdnf. Hence, by employing the chronic mild stress (CMS) paradigm, we studied the role of the Gr beta-RACK1-Bdnf signaling in the different susceptibility to chronic stress exposure. We found that resilience to two weeks of CMS is paralleled by the activation of this pathway in the ventral hippocampus, the hippocampal subregion involved in the modulation of stress response. Moreover, the results we obtained in vitro by exposing SH-SY5Y cells to cortisol support the data we found in vivo. The results obtained add novel critical information about the link among Gr, RACK1 and Bdnf and the resilience to chronic stress, suggesting novel targets for the treatment of stress-related disorders, including depression.