Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II.
Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II.
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DOI：
10.1523/jneurosci.5485-09.2010
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发表时间：
2010-02-03
期刊：
影响因子：
--
通讯作者：
Foster TC
中科院分区：
文献类型：
--
作者：
Bodhinathan K;Kumar A;Foster TC
N-甲基-D-天冬氨酸受体(NMDAR)对突触可塑性的贡献随着年龄的增长而下降，这种下降被认为是导致记忆障碍的原因之一。在这里，我们证明了与年龄相关的细胞内氧化还原状态的改变通过钙/钙调蛋白依赖的蛋白激酶II(CaMKII)导致NMDAR反应的下降。氧化剂黄嘌呤/黄嘌呤氧化酶(X/XO)可降低幼年(3-8mo)大鼠脑片上NMDAR介导的CA3-CA1突触反应，但不能降低老龄(20-25mo)大鼠脑片上NMDAR介导的突触反应。相反，还原剂二硫苏糖醇(DTT)选择性地在更大程度上增强老化海马片的NMDAR反应。NMDAR反应的增强促进了老年动物长时程增强(LTP)的诱导，但对幼年动物没有影响。在α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)介导的突触反应中，未观察到DTT介导的NMDAR反应的增长。细胞内应用膜不通透性还原剂L-谷胱甘肽(L-谷胱甘肽)通过细胞内记录吸管也观察到类似的增加，表明NMDAR反应的增加依赖于细胞内的氧化还原状态。DTT对NMDAR反应的增强依赖于CaMKII活性，并可被CaMKII抑制剂--肉豆蔻酰化自体肌肽-2相关抑制肽(MYR-AIP)所阻断，但不能抑制蛋白磷酸酶-PP1和钙调神经磷酸酶(CaN/PP2B)或蛋白激酶C的活性。CaMKII活性测定表明，DTT可提高老年动物CA1细胞胞浆提取液中CaMKII的活性，但对幼年动物无此作用。这些发现表明，CaMKII在衰老过程中的氧化，NMDAR反应的下降，以及突触可塑性的改变之间存在联系。
The contribution of the N-methyl D-aspartate receptors (NMDARs) to synaptic plasticity declines during aging and the decline is thought to contribute to memory deficits. Here, we demonstrate that an age-related shift in intracellular redox state contributes to the decline in NMDAR responses through Ca2+/calmodulin-dependent protein kinase II (CaMKII). The oxidizing agent xanthine/xanthine oxidase (X/XO) decreased the NMDAR mediated synaptic responses at hippocampal CA3-CA1 synapses in slices from young (3–8 mo), but not aged (20–25 mo) rats. Conversely, the reducing agent dithiothreitol (DTT) selectively enhanced NMDAR response to a greater extent in aged hippocampal slices. The enhancement of NMDAR responses facilitated induction of long-term potentiation (LTP) in aged but not young animals. The DTT-mediated growth in the NMDAR response was not observed for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) mediated synaptic responses. A similar increase was observed by intracellular application of the membrane impermeable reducing agent, L-glutathione (L-GSH), through the intracellular recording pipette, indicating the increased NMDAR response was dependent on intracellular redox state. DTT enhancement of the NMDAR response was dependent on CaMKII activity and was blocked by the CaMKII inhibitor – myristoylated autocamtide-2 related inhibitory peptide (myr-AIP), but not by inhibition of the activity of protein phosphatases - PP1 and calcineurin (CaN/PP2B) or protein kinase C. CaMKII activity assays established that DTT increased CaMKII activity in CA1 cytosolic extracts in aged but not in young animals. These findings indicate a link between oxidation of CaMKII during aging, a decline in NMDAR responses, and altered synaptic plasticity.