aspase-3调控Akt/GSK-3β信号通路在铝致大鼠在体长时程增强损伤中的作用机制

mount of studies have indicated that aluminum exposure could impair learning and memory function in human population and animal models. The ability of Al to inhibit hippocampal long-term potentiation (LTP) ,which is one of phenomena underlying synaptic plasticity, hints possibility of Al impairing synaptic plasticity. LTP is dependent on the insertion (exocytosis) of AMPA receptors to synaptic membrane, Akt/GSK-3β signaling pathway has been demonstrated to mediate AMPAR delivery in the hippocampus and LTP, and a mechanism that caspase-3 can cleave Akt is involved in synaptic plasticity, but the underlying molecular mechanism among them is still not elucidated. To investigate the mechanism of LTP impairment and related signal pathway variations induced by Al exposure, SD rats were randomly distributed into 6 groups and treated intracerebroventricularly injection with Al(mal)3 and caspase-3 inhibitor z-DEVD-fmk at different doses, protein levels of active caspase-3, Akt and GSK-3β were also detected. Al treatment produced dose-dependent suppression of LTP and dose-dependent decreases of AMPAR subunits GluR1 and GluR2 in the membrane extracts and the total extracts. The AMPA receptor proteins were degraded and trafficking of AMPA receptor subunits to synaptic membrane sites during HFS-induced LTP was suppressed. Al administration caused a increased accumulation of active caspase-3 and a gradual decrease of Akt and p-GSK-3β. Interestingly, at the same time z-DEVD-fmk significantly reversed both the Al induced increase of active caspase-3 and suppression of LTP. Furthermore, z-DEVD-fmk also reversed the decrease of the protein content of GluR1 and GluR2 in both the total and membrane- enriched extracts. More importantly, z-DEVD- fmk effectively reversed Al induced decrease of Akt and p-GSK-3β. Taken all the results together, Al depressed LTP and AMPAR contents, while z-DEVD-fmk reversed Al-induced LTP depression, increase of active caspase-3, decrese of AMPAR contents, and decrease of Akt and p-GSK-3β. Our findings clarified the underlying mechanism between Al-induced LTP impairment and related signal pathways, ie. activation of casapse-3 - cleavage of Akt -reduction of phosphorylation of GSK-3β- activation of GSK-3β- internalization of AMPAR - inhibiton of externalization of AMPAR, and finally impairment of LTP.