Kumar Ashok, Thinschmidt Jeffrey S, Foster Thomas C
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611, USA.
Aging (Albany NY). 2019 Jul 24;11(14):5140-5157. doi: 10.18632/aging.102108.
We examined the contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the redox-mediated decline in NMDAR function during aging. GluN2A and GluN2B selective antagonists decreased peak NMDAR currents to a similar extent in young and aged animals, indicating that a shift in diheteromeric GluN2 subunits does not underlie the age-related decrease in the NMDAR synaptic function. Application of dithiothreitol (DTT) in aged animals, increased peak NMDAR synaptic currents, prolonged the decay time, and increased the sensitivity of the synaptic response to the GluN2B antagonist, ifenprodil, indicating that DTT increased the contribution of GluN2B subunits to the synaptic response. The DTT-mediated increase in NMDAR function was inhibited by partial blockade of NMDARs, and this inhibition was rescued by increasing Ca concentration in the recording medium. The results indicate that DTT-mediated potentiation requires Ca influx through NMDAR activity. Finally, redox regulation of NMDAR function depends on the activity of Ca/calmodulin-dependent protein kinase II (CaMKII). The results indicate that activity-dependent NMDAR synaptic plasticity is suppressed by redox-mediated inhibition of CaMKII activation during aging. The redox regulation of NMDARs represents a suppression of a metaplasticity mechanism, which can disrupt synaptic plasticity and cognition associated with neurological or psychiatric diseases, and aging.
我们研究了N-甲基-D-天冬氨酸受体（NMDAR）亚基在衰老过程中氧化还原介导的NMDAR功能衰退中的作用。GluN2A和GluN2B选择性拮抗剂在年轻和老年动物中使NMDAR电流峰值下降的程度相似，这表明二聚体GluN2亚基的转变并非NMDAR突触功能随年龄下降的基础。在老年动物中应用二硫苏糖醇（DTT），可增加NMDAR突触电流峰值，延长衰减时间，并增加突触反应对GluN2B拮抗剂ifenprodil的敏感性，这表明DTT增加了GluN2B亚基对突触反应的贡献。NMDAR的部分阻断抑制了DTT介导的NMDAR功能增强，而在记录介质中增加钙浓度可挽救这种抑制作用。结果表明，DTT介导的增强作用需要通过NMDAR活性的钙内流。最后，NMDAR功能的氧化还原调节取决于钙/钙调蛋白依赖性蛋白激酶II（CaMKII）的活性。结果表明，衰老过程中氧化还原介导的CaMKII激活抑制抑制了依赖活性的NMDAR突触可塑性。NMDAR的氧化还原调节代表了对一种元可塑性机制的抑制，这种机制可能会破坏与神经或精神疾病以及衰老相关的突触可塑性和认知。
