title: Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase.
abstract: An increased level of glucocorticoid may be related to the pathophysiology of depressive disorder. The involvement of brain-derived neurotrophic factor (BDNF) in the antidepressive effect has also been suggested; however, the possible influence of glucocorticoid on the action of BDNF in the developing central nervous system has not been elucidated. In this study, we investigated the effect of glucocorticoid (dexamethasone, DEX) on synaptic maturation and function enhanced by BDNF in early developing hippocampal neurons. In the immature stage, BDNF increased the outgrowth of dendrites and the expression of synaptic proteins including glutamate receptors and presynaptic proteins. Pretreatment with DEX significantly inhibited the BDNF-dependent up-regulation of both dendritic outgrowth and synaptic proteins. In the more mature stage, the BDNF-reinforced postsynaptic Ca(2+) influx was decreased by DEX. BDNF-enhanced presynaptic glutamate release was also suppressed. RU486, a glucocorticoid receptor antagonist, canceled the DEX-dependent blocking effect on the action of BDNF. After down-regulation of glucocorticoid receptor by small interfering RNA application, no inhibitory effect of DEX on the BDNF-increased synaptic proteins was observed. Interestingly, the BDNF-activated MAPK/ERK pathway, which is an essential intracellular signaling pathway for the BDNF-increased synaptic proteins, was reduced by DEX. These results suggest that BDNF-mediated synaptic maturation is disturbed after neurons are exposed to high-level glucocorticoid in their development stage.
authors: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
authors: Emi
authors: E
authors: Kumamaru
authors: Tadahiro
authors: T
authors: Numakawa
authors: Naoki
authors: N
authors: Adachi
authors: Yuki
authors: Y
authors: Yagasaki
authors: Aiko
authors: A
authors: Izumi
authors: Madinyet
authors: M
authors: Niyaz
authors: Motoshige
authors: M
authors: Kudo
authors: Hiroshi
authors: H
authors: Kunugi
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D015151:Immunoblotting; D015735:Mifepristone / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D005938:Glucocorticoids; D006727:Hormone Antagonists; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C113580:U 0126; D015735:Mifepristone; D018698:Glutamic Acid; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium