Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments.
Activation of glycogen synthase kinase-3 (GSK-3) can cause memory deficits as seen in Alzheimer's disease, the most common age-associated dementia, but the mechanism is not understood. Here, we found that activation of GSK-3 by wortmannin or transient overexpression of wild-type GSK-3beta could suppress the induction of long-term potentiation (LTP) in rat hippocampus, whereas simultaneous inhibition of GSK-3 by lithium or SB216763 or transient expression of a dominant-negative GSK-3beta mutant (dnGSK-3beta) preserved the LTP. After high-frequency stimulation (HFS), the presynaptic release of glutamate and the expression/clustering of synapsin I, a synaptic vesicle protein playing an important role in neurotransmitter release, decreased markedly after upregulation of GSK-3. In vitro studies further demonstrated that GSK-3 inhibited the expression of SynI independent of HFS. In postsynaptic level, the expression of PSD93 and NR2A/B proteins decreased significantly when GSK-3 was activated. The LTP-associated synapse impairments including less presynaptic active zone, thinner postsynaptic density, and broader synaptic cleft were also prominent in the hippocampal slices after HFS with activation of GSK-3. These synaptic impairments were attenuated when GSK-3 was simultaneously inhibited by LiCl or SB216763 or transient expression of dnGSK-3. We conclude that upregulation of GSK-3 impairs the synaptic plasticity both functionally and structurally, which may underlie the GSK-3-involved memory deficits.
Zhu
Ling-Qiang
LQ
Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Wang
Shao-Hui
SH
Liu
Dan
D
Yin
Yang-Yang
YY
Tian
Qing
Q
Wang
Xiao-Chuan
XC
Wang
Qun
Q
Chen
Jian-Guo
JG
Wang
Jian-Zhi
JZ
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*
D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3