Chen Zhicheng, Stockwell Jocelyn, Cayabyab Francisco S
Laboratory for Neurodegenerative Research, Brigham & Women's Hospital and Harvard Institutes of Medicine, Room 931, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA.
Department of Surgery, Neuroscience Research Group, College of Medicine, Room GD30.5, D-Wing Health Science Building, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
Neurochem Res. 2016 May;41(5):1085-97. doi: 10.1007/s11064-015-1799-3. Epub 2015 Dec 23.
Aging causes multiple changes in the mammalian brain, including changes in synaptic signaling. Previous reports have shown increased extracellular adenosine in the aging brain, and we recently reported that activation of adenosine A1 receptors (A1Rs) induces AMPA receptor (AMPAR) internalization in rat hippocampus. This study investigated whether aging-related changes in the rat hippocampus include altered surface expression of adenosine A1 and A2A receptors, and whether these changes correspond to changes in AMPAR surface expression and altered synaptic plasticity. We found reduced A1R surface expression in middle-aged rat hippocampus, and also reduced GluA1 and GluA2 AMPAR subunit surface expression. Using a chemically-induced LTP (cLTP) experimental protocol, we recorded fEPSPs in young (1 month old) and middle-aged (7-12 month old) rat hippocampal slices. There were significant impairments in cLTP in middle-aged slices, suggesting impaired synaptic plasticity. Since we previously showed that the A1R agonist N(6)-cyclopentyladenosine (CPA) reduced both A1Rs and GluA2/GluA1 AMPARs, we hypothesized that the observed impaired synaptic plasticity in middle-aged brains is regulated by A1R-mediated AMPAR internalization by clathrin-mediated endocytosis. Following cLTP, we found a significant increase in GluA1 and GluA2 surface expression in young rats, which was blunted in middle-aged brains or in young brains pretreated with CPA. Blocking A1Rs with 8-cyclopentyl-1,3-dipropylxanthine or AMPAR endocytosis with either Tat-GluA2-3Y peptide or dynasore (dynamin inhibitor) similarly enhanced AMPAR surface expression following cLTP. These data suggest that age-dependent alteration in adenosine receptor expression contributes to increased AMPAR endocytosis and impaired synaptic plasticity in aged brains.
衰老会导致哺乳动物大脑发生多种变化，包括突触信号传导的改变。先前的报道显示，衰老大脑中的细胞外腺苷增加，并且我们最近报道，腺苷A1受体（A1Rs）的激活会诱导大鼠海马体中的AMPA受体（AMPAR）内化。本研究调查了大鼠海马体中与衰老相关的变化是否包括腺苷A1和A2A受体的表面表达改变，以及这些变化是否与AMPAR表面表达的变化和突触可塑性改变相对应。我们发现中年大鼠海马体中A1R表面表达降低，同时GluA1和GluA2 AMPAR亚基表面表达也降低。使用化学诱导的长时程增强（cLTP）实验方案，我们在年轻（1个月大）和中年（7 - 12个月大）大鼠海马体切片中记录了场兴奋性突触后电位（fEPSPs）。中年切片中的cLTP存在显著损伤，表明突触可塑性受损。由于我们之前表明A1R激动剂N(6)-环戊基腺苷（CPA）会降低A1Rs以及GluA2/GluA1 AMPARs，我们推测中年大脑中观察到的突触可塑性受损是由网格蛋白介导的内吞作用通过A1R介导的AMPAR内化来调节的。在cLTP之后，我们发现年轻大鼠中GluA1和GluA2表面表达显著增加，而在中年大脑或用CPA预处理的年轻大脑中这种增加受到抑制。用8 - 环戊基 - 1,3 - 二丙基黄嘌呤阻断A1Rs或用Tat - GluA2 - 3Y肽或dynasore（动力蛋白抑制剂）阻断AMPAR内吞作用，同样会在cLTP后增强AMPAR表面表达。这些数据表明，腺苷受体表达的年龄依赖性改变导致老年大脑中AMPAR内吞作用增加和突触可塑性受损。
