Department of Neurophysiology, Kagawa School of Pharmaceutical Sciences and Institute of Neuroscience, Tokushima Bunri University, Kagawa, Japan.
J Neurophysiol. 2011 Jun;105(6):2897-906. doi: 10.1152/jn.00287.2010. Epub 2011 Apr 6.
N-methyl-D-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABA(A) receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.
N-甲基-D-天冬氨酸（NMDA）受体（NMDARs）参与突触可塑性和谷氨酸能兴奋性传递的调节。NMDA 受体的激活对抑制性 GABA 能传递的影响在很大程度上仍不清楚。在这里，我们报告说，NMDA 的短暂应用可以在小鼠海马切片中的 CA1 锥体神经元中诱导两种截然不同的作用：1）一种内向电流归因于突触后 NMDA 受体的激活；2）快速相突触电流，即 GABA（A）受体介导的自发性抑制性突触后电流（sIPSCs）。sIPSCs 的平均幅度也被 NMDA 增加。NMDA 显著抑制 sIPSC 频率和幅度的这种深刻增加，而微小 IPSC 的频率和平均幅度不受 NMDA 的显著影响，表明 NMDA 引起 GABA 能中间神经元的重复放电，从而导致单个 GABA 能轴突的多个突触部位释放 GABA。我们发现，记录的锥体神经元中注入的 NMDA 开放通道阻滞剂 MK-801 抑制了 NMDA 诱导的 sIPSCs 的增加，这表明中间神经元的放电可能不是唯一因素，某些逆行信使也可能参与 NMDA 介导的 GABA 能传递增强。我们的药理学测试结果表明，CA1 锥体神经元中 NMDA 受体的激活动员了一氧化氮信号通路，从而逆行促进了来自突触前末端的 GABA 释放。因此，谷氨酸能突触上的 NMDA 受体（无论是在 CA1 锥体神经元上还是在中间神经元上）似乎都对确定海马微电路的尖峰时间施加反馈和前馈抑制。
