Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation.
The induction of hippocampal long-term synaptic plasticity is exquisitely sensitive to behavioral stress, but the underlying mechanisms are still unclear. We report here that hippocampal slices prepared from adult rats that had experienced unpredictable and inescapable restraint tail-shock stress showed marked impairments of long-term potentiation (LTP) in the CA1 region. The same stress promoted the induction of long-term depression (LTD). These effects were prevented when the animals were given the glucocorticoid receptor antagonist 11beta, 17beta-11[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-estra-4-9-dien-3-one before the stress. Immunoblotting analyses revealed that stress induced a profound and prolonged extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK1/2 MAPK) hyperphosphorylation through small GTPase Ras, Raf-1, and MAPK kinase 1/2 (MEK1/2). Furthermore, the stress effects were obviated by the intrahippocampal injection of specific inhibitors of MEK1/2 (U0126), protein kinase C (bisindolylmaleimide I), tyrosine kinase (K252a), and BDNF antisense oligonucleotides. These results suggest that the effects of stress on LTP and LTD originate from the corticosterone-induced sustained activation of ERK1/2-coupled signaling cascades.
Yang
Chih-Hao
CH
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Huang
Chiung-Chun
CC
Hsu
Kuei-Sen
KS
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D003345:Corticosterone / Q000097:blood / Q000502:physiology*; D004597:Electroshock; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology*
D019208:Brain-Derived Neurotrophic Factor; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000324:Adrenocorticotropic Hormone; D020813:Receptor, trkB; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D003345:Corticosterone