Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter

An increase in glucocorticoid levels and down-regulation of BDNF (brain-derived neurotrophic factor) are supposed to be involved in the pathophysiology of depressive disorders. However, possible crosstalk between glucocorticoid- and BDNF-mediated neuronal functions in the CNS has not been elucidated. Here, we examined whether chronic glucocorticoid exposure influences BDNF-triggered intracellular signaling for glutamate release via a glutamate transporter. We found that chronic exposure to dexamethasone (DEX, a synthetic glucocorticoid) suppressed BDNF-induced glutamate release via weakening the activation of the PLC-γ (phospholipase C-γ)/Ca²⁺ system in cultured cortical neurons. We demonstrated that the GR (glucocorticoid receptor) interacts with receptor tyrosine kinase for BDNF (TrkB). Following DEX treatment, TrkB-GR interaction was reduced due to the decline in GR expression. Corticosterone, a natural glucocorticoid, also reduced TrkB-GR interaction, BDNF-stimulated PLC-γ, and BDNF-triggered glutamate release. Interestingly, BDNF-dependent binding of PLC-γ to TrkB was diminished by DEX. SiRNA transfection to induce a decrease in endogenous GR mimicked the inhibitory action of DEX. Conversely, DEX-inhibited BDNF-activated PLC-γ signaling for glutamate release was recovered by GR overexpression. We propose that TrkB-GR interaction plays a critical role in the BDNF-stimulated PLC-γ pathway, which is required for glutamate release, and the decrease in TrkB-GR interaction caused by chronic exposure to glucocorticoids results in the suppression of BDNF-mediated neurotransmitter release via a glutamate transporter.