The synergistic effects on neuronal plasticity of acute glucocorticoids levels increase 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.In this study we investigated in vitro the molecular mechanisms underlying the interplay of glucocorticoids and TRKB signaling. We found that the glucocorticoid receptor physically interacts with TRKB, modulating its dimerization and activity both in presence and in absence of glucocorticoids. Additionally, the transmembrane domain of TRKB is important for the interaction and for an effective signaling of the receptor, suggesting an overlap between the two signaling pathway.These results shed light on the interconnected effects of glucocorticoids and TRKB signaling both in physiological and in pathological condition, highlighting the need for a more comprehensive understanding of the role and the dysfunction of different cellular players contributing to synaptic plasticity.