Redox modulation of long-term potentiation in the hippocampus via regulation of the glycogen synthase kinase-3beta pathway.
Alzheimer disease (AD) is an age-related neurodegenerative disorder. Many observations indicate that impaired redox regulation is implicated in AD with synaptic failure. The aim of the current investigation was to characterize the role of redox-active agents on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices and to elucidate the molecular sequence of events leading to these changes. The results presented here indicate that the membrane-permeable oxidizing agent chloramine-T (CH-T) inhibits the induction of LTP, whereas the membrane-permeable reducing agent dithiothreitol (DTT) enhances the induction of LTP. In contrast, neither the membrane-impermeable oxidizing agent 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) nor the membrane-impermeable reducing agent tris-(2-carboxyethyl) phosphine (TCEP) can affect the induction of LTP. The inhibition of LTP by CH-T can be restored by pretreatment with DTT but not with TCEP, whereas the enhancement of LTP by DTT can be reversed by pretreatment with CH-T but not with DTNB. We also provide evidence that the CH-T-evoked inhibition of LTP is mediated via activation of glycogen synthase kinase-3beta (GSK-3beta), whereas the DTT-evoked enhancement of LTP is mediated via inactivation of GSK-3beta. These findings will benefit the understanding of the redox contribution to the mechanisms underlying synaptic plasticity and AD pathogenesis.
Cai
Fei
F
Department of Pharmacology, Tongji Medical College, Wuhan, Hubei 430030, China.
Wang
Fang
F
Lin
Fan-Kai
FK
Liu
Chao
C
Ma
Li-Qun
LQ
Liu
Jue
J
Wu
Wen-Ning
WN
Wang
Wei
W
Wang
Jiang-Hua
JH
Chen
Jian-Guo
JG
D000818:Animals; D015153:Blotting, Western; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008839:Microelectrodes; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019163:Reducing Agents / Q000494:pharmacology*
D016877:Oxidants; D019163:Reducing Agents; D038362:Glycogen Synthase Kinase 3