Glucocorticoid Receptor Interacts with the TRKB Transmembrane Domain and modulates TRKB Dimerization and Neuronal...

The overlapping effects on neuronal plasticity of acute increase in glucocorticoid levels and the BDNF-TRKB signaling indicate a deep interconnection between the two pathways. Moreover, chronic stress with elevated glucocorticoids levels and downregulation of TRKB signaling associated with reduced BDNF are both involved in the pathophysiology of different psychiatric disorders. However, the mechanism by which TRKB and glucocorticoid receptors are recruited together in the modulation of neuronal plasticity is not clear yet. In this study we investigated the molecular mechanisms underlying the interplay of glucocorticoids and TRKB signaling in vitro and in vivo. We found that although not binding directly to TRKB, glucocorticoids promote TRKB dimerization and signaling similarly to BDNF. Moreover, the glucocorticoid receptor physically interacts with TRKB, modulating its dimerization and activity both in presence and in absence of glucocorticoids and contributing to TRKB-mediated plasticity. The transmembrane domain of TRKB is important for the interaction and for mediating the behavioral effects of TRKB and glucocorticoid receptor modulation, suggesting at least a partial overlap between the two signaling pathways. These results shed light on the interconnected effects of glucocorticoid and TRKB signaling highlighting the need for a more comprehensive understanding of the role and the dysfunction of different players contributing to synaptic plasticity.