Postsynaptic NO/cGMP Increases NMDA Receptor Currents via Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Hippocampus
Postsynaptic NO/cGMP Increases NMDA Receptor Currents via Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Hippocampus
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DOI：
10.1093/cercor/bht048
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发表时间：
2014-07-01
期刊：
影响因子：
3.7
通讯作者：
Mittmann, Thomas
中科院分区：
文献类型：
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作者：
Neitz, Angela;Mergia, Evanthia;Mittmann, Thomas
一氧化氮（NO）/环磷酸鸟苷（cGMP）信号级联参与突触传递的调节。NO的作用是由对NO敏感的形成cGMP的鸟苷酸环化酶（NO - GCs）介导的，它存在两种亚型，其调节特性难以区分。在缺乏任何一种NO - GC亚型的基因敲除（KO）小鼠中长时程增强（LTP）缺失，这表明两种NO - GCs都对LTP有贡献。最近，我们发现NO - GC1亚型位于谷氨酸能神经元的突触前，通过海马中的超极化激活环核苷酸（HCN）门控通道增加谷氨酸的释放。对全细胞记录中海马CA1神经元的电生理分析显示，在NO - GC2基因敲除小鼠中HCN电流减少，激活曲线发生超极化移位，同时静息膜电位降低。这些特征在野生型（WT）神经元中使用NO - GC抑制剂可模拟出来。对谷氨酸受体的分析显示，在NO - GC2基因敲除小鼠中NMDA受体电流呈cGMP依赖性降低，在野生型中通过抑制HCN通道可模拟这一现象。降低细胞外Mg²⁺会增加NO - GC2基因敲除小鼠中NMDA受体电流，并使在生理Mg²⁺条件下缺失的LTP得以诱导。总之，我们的数据表明，突触后cGMP通过门控HCN通道增加N - 甲基 - D - 天冬氨酸（NMDA）受体电流，因此是LTP所必需的。
The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiological analysis of hippocampal CA1 neurons in whole-cell recordings revealed a reduction of HCN currents and a hyperpolarizing shift of the activation curve in the NO-GC2 KOs associated with reduced resting membrane potentials. These features were mimicked in wild-type (WT) neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in the NO-GC2 KO mice, which was mimicked in WT by HCN channel inhibition. Lowering extracellular Mg2+ increased NMDA receptor currents in the NO-GC2 KO and allowed the induction of LTP that was absent at physiological Mg2+. In sum, our data indicate that postsynaptic cGMP increases the N-methyl-d-aspartate (NMDA) receptor current by gating HCN channels and thereby is required for LTP.