Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability.
Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability.
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DOI：
10.1523/jneurosci.0455-06.2006
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发表时间：
2006-04-26
影响因子：
5.3
通讯作者：
Hardingham, Giles E
中科院分区：
文献类型：
--
作者：
Soriano, Francesc X;Papadia, Sofia;Hofmann, Frank;Hardingham, Neil R;Bading, Hilmar;Hardingham, Giles E
低剂量的NMDA可以诱导神经保护作用，其激活突触和突触外NMDA受体。这显然与我们最近的研究结果相矛盾，即突触外NMDA受体信号对突触NMDA受体的促生存信号产生显性抑制作用。在这里，我们报告说，暴露于低预处理剂量的NMDA的结果在优先激活的突触NMDA受体，因为一个显着增加动作电位放电。面对凋亡或兴奋性毒性损伤的神经保护的急性和长期阶段都依赖于这种放电增强。突触NMDA受体依赖性神经保护的关键介质，磷脂酰肌醇3激酶-Akt（PI 3激酶-Akt）信号传导至叉头盒亚群O（FOXO）输出和糖原合成酶激酶3β（GSK 3 β）抑制以及脑源性神经营养因子（BDNF）的cAMP反应元件结合蛋白依赖性（CREB依赖性）激活，仅可由低剂量的NMDA通过这种动作电位依赖性途径诱导。相反，毒性阈值另一侧的NMDA剂量不利于突触NMDA受体激活，因为它们强烈抑制放电率低于基线。经典的钟形曲线描绘了神经元的命运，响应于NMDA剂量可以被视为两个拮抗（突触与突触外）曲线的净效应：通过增加发射的突触信号在低剂量下占主导地位，而发射成为抑制和突触外信号占主导地位的毒性阈值被交叉。
Neuroprotection can be induced by low doses of NMDA, which activate both synaptic and extrasynaptic NMDA receptors. This is in apparent contradiction with our recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we report that exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing. Both acute and long-lasting phases of neuroprotection in the face of apoptotic or excitotoxic insults are dependent on this firing enhancement. Key mediators of synaptic NMDA receptor-dependent neuroprotection, phosphatidylinositol 3 kinase-Akt (PI3 kinase-Akt) signaling to Forkhead box subgroup O (FOXO) export and glycogen synthase kinase 3β (GSK3β) inhibition and cAMP response element-binding protein-dependent (CREB-dependent) activation of brain-derived neurotrophic factor (BDNF), can be induced only by low doses of NMDA via this action potential-dependent route. In contrast, NMDA doses on the other side of the toxicity threshold do not favor synaptic NMDA receptor activation because they strongly suppress firing rates below baseline. The classic bell-shaped curve depicting neuronal fate in response to NMDA dose can be viewed as the net effect of two antagonizing (synaptic vs extrasynaptic) curves: via increased firing the synaptic signaling dominates at low doses, whereas firing becomes suppressed and extrasynaptic signaling dominates as the toxicity threshold is crossed.