Tonic and phasic nitric oxide signals in hippocampal long-term potentiation
Tonic and phasic nitric oxide signals in hippocampal long-term potentiation
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DOI：
10.1523/jneurosci.2259-06.2006
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发表时间：
2006-11-08
影响因子：
5.3
通讯作者：
Garthwaite, John
中科院分区：
文献类型：
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作者：
Hopper, Rachel A.;Garthwaite, John
一氧化氮（NO）参与长时程增强（LTP）和其他形式的突触可塑性在许多不同的大脑区域，但它的来源和如何作用仍然存在争议。利用大鼠和小鼠海马切片，我们验证了强直和相位NO信号是必需的，并且它们来自不同的NO合成酶异构体的假设。NMDA增加一氧化氮生成的方式被三种不同的神经元一氧化氮合成酶（nNOS）抑制剂有效抑制。通过敏化胍基环化酶偶联NO受体，可以监测补品NO，从而可以通过cGMP测量检测到非常低的环境NO浓度。NMDA受体、nNOS或诱导NO合成酶（iNOS）的抑制不影响其水平。在蛋白质或活性分析中也检测不到iNOS。补益型NO易受内皮NO合成酶（eNOS）抑制剂的影响，eNOS敲除小鼠缺乏补益型NO。eNOS敲除表现出LTP的缺陷，类似于用NO合酶抑制剂处理的野生型。外源性低水平一氧化氮可以完全恢复敲除后的LTP。nNOS的抑制也导致LTP的主要损失，特别是晚期LTP的损失。同样，外源性NO可以补偿，但与eNOS敲除中恢复LTP的浓度相比，需要更高的浓度。由此可见，海马LTP均需要强直性NO信号和相性NO信号，二者分别由eNOS和nNOS产生，前者在血管中产生，后者在神经元中产生。
Nitric oxide ( NO) participates in long-term potentiation (LTP) and other forms of synaptic plasticity in many different brain areas but where it comes from and how it acts remain controversial. Using rat and mouse hippocampal slices, we tested the hypothesis that tonic and phasic NO signals are needed and that they derive from different NO synthase isoforms. NMDA increased NO production in a manner that was potently inhibited by three different neuronal NO synthase ( nNOS) inhibitors. Tonic NO could be monitored after sensitizing guanylyl cyclase-coupled NO receptors, allowing the very low ambient NO concentrations to be detected by cGMP measurement. The levels were unaffected by inhibition of NMDA receptors, nNOS, or the inducible NO synthase ( iNOS). iNOS was also undetectable in protein or activity assays. Tonic NO was susceptible to agents inhibiting endothelial NO synthase ( eNOS) and was missing in eNOS knock-out mice. The eNOS knock-out sexhibited a deficiency in LTP resembling that seen in wild-types treated with a NO synthase inhibitor. LTP in the knock-outs could be fully restored by supplying a low level of NO exogenously. Inhibition of nNOS also caused a major loss of LTP, particularly of late-LTP. Again, exogenous NO could compensate, but higher concentrations were needed compared with those restoring LTP in the eNOS knock-outs. It is concluded that tonic and phasic NO signals are both required for hippocampal LTP and the two are generated, respectively, by eNOS and nNOS, the former in blood vessels and the latter in neurons.