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Abstract
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Growing evidence has suggested a close relationship between BDNF and the pathophysiology of depression. The BDNF level was low in the brains of suicide victims, most of whom had depressive disorders. BDNF plays a critical role in cognition, learning, and memory, and patients with depression exhibit deficits in these brain functions. Both BDNF and glucocorticoids/GR are involved in synaptic function and the pathophysiology of depression. However, the possible influence of glucocorticoids on the acute action of BDNF is poorly understood.
Here we report that chronic treatment with glucocorticoids suppressed BDNF-triggered PLC-γ signaling for glutamate release via a glutamate transporter. We found that the GR interacted with receptor tyrosine kinase for BDNF (TrkB), playing an important role in BDNF action.
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.
Language: en |