Gage A T, Reyes M, Stanton P K
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461-1602, USA.
Hippocampus. 1997;7(3):286-95. doi: 10.1002/(SICI)1098-1063(1997)7:3<286::AID-HIPO4>3.0.CO;2-J.
Long-term depression (LTD) of synaptic strength is induced by glutamate-triggered increases in postsynaptic [Ca2+], through either influx or release from intracellular stores. Induction of LTD has also been reported to require release of Ca2+ from presynaptic stores and activation of presynaptic Ca2+/calmodulin-dependent protein kinase II. This finding leads to the hypothesis that the intercellular messenger nitric oxide (NO) may be a means by which postsynaptic Ca2+ triggers changes expressing LTD in presynaptic terminals. We report that bath application of the oxadiazoloquinoxalone derivative ODQ (4 microM), a selective inhibitor of NO-sensitive guanylyl cyclase (NOGC), markedly attenuated (90%) the magnitude of LTD induced by low-frequency stimulation (LFS; 1 Hz/15 min) of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Both the NO donor S-nitroso-N-acetylpenicillamine (100 microM) and the membrane-permeant cyclic guanine 3',5'-monophosphate (cGMP) analogue 8-(-4-chlorophenylthio) guanosine (8-pCPT)-cGMP (50 microM) enhanced the magnitude of LTD, which is consistent with he hypothesis that activation of NOGC plays a role in the induction of LTD. Nicotinamide (20 mM), an inhibitor of NO-activated ADP ribosyltransferase, did not impair the induction of LTD. In contrast to de novo LTD, the reversal of long-term potentiation by LFS (depotentiation) was only partially blocked (55%) by ODQ, and heterosynaptic LTD was not impaired at all, suggesting that there are both NOGC-dependent and -independent forms of LTD. Because postsynaptic intracellular infusion of ODQ (500 microM) failed to block the induction of LTD, we conclude that activation of presynaptic NOGC is a necessary step in the induction of an NOGC-dependent component of LTD.
突触强度的长期抑制（LTD）是由谷氨酸触发的突触后[Ca2+]增加所诱导的，这种增加可通过细胞外流入或细胞内储存库的释放来实现。据报道，LTD的诱导还需要从突触前储存库释放Ca2+并激活突触前Ca2+/钙调蛋白依赖性蛋白激酶II。这一发现引出了一个假说，即细胞间信使一氧化氮（NO）可能是突触后Ca2+触发突触前终末表达LTD变化的一种方式。我们报告称，在体外海马切片中，浴用恶二唑并喹喔啉酮衍生物ODQ（4 microM），一种对NO敏感的鸟苷酸环化酶（NOGC）的选择性抑制剂，显著减弱（90%）了由低频刺激（LFS；1 Hz/15分钟）诱导的Schaffer侧支-CA1突触LTD的幅度。NO供体S-亚硝基-N-乙酰青霉胺（100 microM）和膜通透性环鸟苷3',5'-单磷酸（cGMP）类似物8-（-4-氯苯硫基）鸟苷（8-pCPT）-cGMP（50 microM）均增强了LTD的幅度，这与NOGC激活在LTD诱导中起作用的假说一致。烟酰胺（20 mM），一种NO激活的ADP核糖基转移酶的抑制剂，并未损害LTD的诱导。与新生LTD相反，LFS对长期增强的逆转（去增强）仅被ODQ部分阻断（55%），而异突触LTD则完全未受损害，这表明存在NOGC依赖性和非依赖性的LTD形式。由于突触后细胞内注入ODQ（500 microM）未能阻断LTD的诱导，我们得出结论，突触前NOGC的激活是诱导LTD的NOGC依赖性成分的必要步骤。
