Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma 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-gamma (phospholipase C-gamma)/Ca(2+) 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-gamma, and BDNF-triggered glutamate release. Interestingly, BDNF-dependent binding of PLC-gamma 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-gamma signaling for glutamate release was recovered by GR overexpression. We propose that TrkB-GR interaction plays a critical role in the BDNF-stimulated PLC-gamma 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.
Numakawa
Tadahiro
T
Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan. numakawa@ncnp.go.jp
Kumamaru
Emi
E
Adachi
Naoki
N
Yagasaki
Yuki
Y
Izumi
Aiko
A
Kunugi
Hiroshi
H
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D018377:Neurotransmitter Agents; D051966:Phospholipase C gamma / Q000378:metabolism*; D051381:Rats; D020239:Receptor Cross-Talk; D020813:Receptor, trkB / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction
D027322:Amino Acid Transport System X-AG; D019208:Brain-Derived Neurotrophic Factor; D005938:Glucocorticoids; D018377:Neurotransmitter Agents; D011965:Receptors, Glucocorticoid; D018698:Glutamic Acid; D020813:Receptor, trkB; D051966:Phospholipase C gamma