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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death.
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In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death.

机译：在发育中的海马神经元中，含有NR2B的N-甲基-D-天冬氨酸受体（NMDARs）可以介导神经元存活和突触增强以及神经元死亡的信号传导。

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It has been suggested that NR2B-containing N-methyl-d-aspartate (NMDA) receptors have a selective tendency to promote pro-death signaling and synaptic depression, compared with the survival promoting, synapse potentiating properties of NR2A-containing NMDA receptors. A preferential localization of NR2A-containing NMDA receptors at the synapse in maturing neurons could thus explain differences in synaptic vs. extrasynaptic NMDA receptor signaling. We have investigated whether NMDA receptors can mediate signaling to survival, death, and synaptic potentiation, in dissociated rat neuronal cultures at a developmental stage prior to significant NR2A expression and subunit-specific differences between synaptic and extrasynaptic NMDA receptors. We show that in developing hippocampal neurons, the progressive reduction in sensitivity of NMDA receptor currents to the NR2B antagonist ifenprodil applies to both synaptic and extrasynaptic locations. However, the reduction is less acute in extrasynaptic currents, indicating that NR2A does partition preferentially, but not exclusively, into synaptic locations at DIV>12. We then studied NMDA receptor signaling at DIV10, when both synaptic and extrasynaptic NMDA receptors are both overwhelmingly and equally NR2B-dominated. To analyze pro-survival signaling we studied the influence of synaptic NMDA receptor activity on staurosporine-induced apoptosis. Blockade of spontaneous NMDAR activity with MK-801, or ifenprodil exacerbated the apoptotic insult. Furthermore, MK-801 and ifenprodil both antagonized neuroprotection promoted by enhancing synaptic activity. Pro-death signaling induced by a toxic dose of NMDA is also blocked by NR2B-specific antagonists. Using a cell culture model of synaptic NMDA receptor-dependent synaptic potentiation, we find that this is mediated exclusively by NR2B-containing N-methyl-D-aspartate receptors, as implicated by NR2B-specific antagonists and the use of selective vs. non-selective doses of the NR2A-preferring antagonist NVP-AAM077. Therefore, within a single neuron, NR2B-NMDA receptors are able to mediate both survival and death signaling, as well as model of NMDA receptor-dependent synaptic potentiation. In this instance, subunit differences cannot account for the dichotomous nature of NMDA receptor signaling.
机译：已经提出，与含有NR2A的NMDA受体的存活促进，突触增强特性相比，含有NR2B的N-甲基-d-天冬氨酸（NMDA）受体具有促进促死亡信号和突触抑制的选择性趋势。含有NR2A的NMDA受体在成熟神经元突触中的优先定位可以解释突触与突触外NMDA受体信号传导的差异。我们已经研究了NMDA受体是否可以在发育阶段，在显着的NR2A表达以及突触和突触外NMDA受体之间的亚基特异性差异之前，介导离体大鼠神经元培养物中的存活，死亡和突触增强信号。我们显示，在发展中的海马神经元中，NMDA受体电流对NR2B拮抗剂ifenprodil敏感性的逐渐降低同时适用于突触和突触外位置。但是，突触外电流的减少并不那么剧烈，这表明NR2A确实优先但非排他地分配到DIV> 12的突触位置。然后，我们研究了DIV10处的NMDA受体信号转导，这时突触和突触外NMDA受体均以压倒性优势且同样以NR2B为主。为了分析生存信号，我们研究了突触NMDA受体活性对星形孢菌素诱导的细胞凋亡的影响。用MK-801或ifenprodil阻断自发NMDAR活性会加剧凋亡。此外，MK-801和艾芬地尔都通过增强突触活性来拮抗神经保护作用。 NR2B特异性拮抗剂也可以阻断由毒性剂量的NMDA诱导的促死亡信号。使用突触NMDA受体依赖性突触增强的细胞培养模型，我们发现这完全是由含NR2B的N-甲基-D-天冬氨酸受体介导的，这与NR2B特异性拮抗剂以及选择性与非选择性的使用有关。选择性剂量的NR2A首选拮抗剂NVP-AAM077。因此，在单个神经元内，NR2B-NMDA受体能够介导生存和死亡信号传导，以及NMDA受体依赖性突触增强模型。在这种情况下，亚基差异不能解释NMDA受体信号传导的二分性。

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