Hawkins R D, Zhuo M, Arancio O
Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University.
J Neurobiol. 1994 Jun;25(6):652-65. doi: 10.1002/neu.480250607.
We have been investigating the hypothesis that the membrane-permeant molecules nitric oxide (NO) and carbon monoxide (CO) may act as retrograde messengers during long-term potentiation (LTP). Inhibitors of either NO synthase or heme oxygenase, the enzyme that produces CO, blocked induction of LTP in the CA1 region of hippocampal slices. Brief application of either NO or CO to slices produced a rapid and long-lasting increase in the size of synaptic potentials if, and only if, the application occurred at the same time as weak tetanic stimulation of the presynaptic fibers. The long-term enhancement by NO or CO was spatially restricted to synapses from active presynaptic fibers and appeared to involve mechanisms utilized by LTP, occluding the subsequent induction of LTP by strong tetanic stimulation. The enhancement by NO or CO was not blocked by the NMDA receptor blocker APV, suggesting that NO and CO act downstream from the NMDA receptor. In other systems, both NO and CO produce many of their effects by activation of soluble guanylyl cyclase and cGMP-dependent protein kinase. An inhibitor of soluble guanylyl cyclase blocked the induction of normal LTP. Conversely, the membrane-permeable analog 8-Br-cGMP produced a rapid onset and long-lasting synaptic enhancement if, and only if, it was applied at the same time as weak presynaptic stimulation. Similarly, two inhibitors of cGMP-dependent protein kinase blocked the induction of normal LTP, and a selective activator of cGMP-dependent protein kinase produced activity-dependent long-lasting synaptic enhancement. 8-Br-cGMP also produced an activity-dependent, long-lasting increase in the amplitude of evoked synaptic currents between pairs of hippocampal neurons in dissociated cell culture. In addition, 8-Br-cGMP, like NO, produced a long-lasting increase in the frequency of spontaneous miniature synaptic currents. These results are consistent with the hypothesis that NO and CO, either alone or in combination, serve as retrograde messengers that produce activity-dependent presynaptic enhancement, perhaps by stimulating soluble guanylyl cyclase and cGMP-dependent protein kinase, during LTP in hippocampus.
我们一直在研究这样一种假说，即膜通透性分子一氧化氮（NO）和一氧化碳（CO）在长时程增强（LTP）过程中可能作为逆行信使发挥作用。一氧化氮合酶或血红素加氧酶（产生CO的酶）的抑制剂，会阻断海马切片CA1区LTP的诱导。仅当在对突触前纤维进行弱强直刺激的同时施加NO或CO时，将其短暂施加于切片会使突触电位的幅度迅速且持久地增加。NO或CO引起的长期增强在空间上局限于来自活跃突触前纤维的突触，并且似乎涉及LTP所利用的机制，从而抑制了随后强强直刺激对LTP的诱导。NO或CO引起的增强作用不会被NMDA受体阻断剂APV所阻断，这表明NO和CO在NMDA受体的下游发挥作用。在其他系统中，NO和CO都通过激活可溶性鸟苷酸环化酶和cGMP依赖性蛋白激酶产生许多效应。可溶性鸟苷酸环化酶的抑制剂会阻断正常LTP的诱导。相反，膜通透性类似物8-溴-cGMP仅在与弱突触前刺激同时施加时，才会迅速起效并产生持久的突触增强。同样，两种cGMP依赖性蛋白激酶的抑制剂会阻断正常LTP的诱导，而cGMP依赖性蛋白激酶的选择性激活剂会产生依赖于活动的持久突触增强。8-溴-cGMP还使解离细胞培养中的海马神经元对之间诱发的突触电流幅度产生依赖于活动的持久增加。此外，8-溴-cGMP与NO一样，使自发微小突触电流的频率产生持久增加。这些结果与以下假说一致，即在海马LTP过程中，NO和CO单独或联合作为逆行信使，可能通过刺激可溶性鸟苷酸环化酶和cGMP依赖性蛋白激酶来产生依赖于活动的突触前增强。
