title: Caspase-3 is Involved in Aluminum-Induced Impairment of Long-Term Potentiation in Rats Through the Akt/GSK-3β Pathway.
abstract: A number of studies have indicated that aluminum (Al) exposure can impair learning and memory function. The ability of Al to inhibit hippocampal long-term potentiation (LTP) suggests the possibility of Al impairing synaptic plasticity. LTP is dependent on the externalization of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR). The protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β) signaling pathway has been demonstrated to mediate AMPAR delivery. A mechanism by which caspase-3 cleaves Akt is involved in synaptic plasticity, but the underlying molecular mechanism involved has still not been elucidated. The purpose of this study was to investigate the mechanism of LTP impairment and the related signaling pathway disturbance induced by Al exposure. Our results reveal that Al treatment produces a dose-dependent suppression of LTP and decreases in the AMPAR subunits GluR1 and GluR2, in both membrane and total cell extracts. Al caused increased accumulation of active caspase-3 and a gradual decrease in Akt and pGSK-3β. Interestingly, Al depressed LTP and AMPAR protein concentration. N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (a caspase-3 inhibitor) reversed the Al-induced LTP inhibition, increased levels of active caspase-3, and decreased AMPAR levels in both total and membrane-enriched extracts. It also decreased Akt and pGSK-3β. The molecular mechanism of Al-induced LTP impairment might be related to the activation of caspase-3, cleavage of Akt, activation of GSK-3β, and inhibition of the externalization of AMPAR.
authors.affiliation: Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. niuqiao55@163.com.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Niu
mesh_terms: D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D001703:Biophysics; D056547:CA1 Region, Hippocampal / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000535:Aluminum; D053148:Caspase 3; D004791:Enzyme Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D009842:Oligopeptides; D051058:Oncogene Protein v-akt; D018091:Receptors, AMPA; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPA receptor; Akt/GSK-3β; Aluminum; Caspase-3; Long-term potentiation