Neurobiology Sector, International School for Advanced Studies (SISSA), Via Beirut 2-4, 34014 Trieste, Italy.
Neuropharmacology. 2010 Mar-Apr;58(4-5):806-15. doi: 10.1016/j.neuropharm.2009.12.003. Epub 2009 Dec 24.
Extracellular field potentials (fEPSPs) and whole cell patch-clamp recordings were used to test the effect of S 38232, a newly developed potent non-alpha7 nicotinic acetylcholine receptors (nAChR) agonist, on synaptic transmission in hippocampal slices obtained from adult mice. S 38232 increased the amplitude of fEPSPs, evoked in stratum radiatum by Schaffer collateral stimulation. This effect was potentiated by picrotoxin, suggesting that S 38232 exerts at least in part its effect on GABAergic interneurons. The action of S 38232 was mediated by non-alpha7 containing nAChRs since it was prevented by DHbetaE (1muM) but not by alpha-BTX (100nM). A similar potentiating effect on fEPSPs was observed when nicotine (1muM) was applied to hippocampal slices obtained from alpha7 -/- mice in the presence of picrotoxin. The potentiating effect of S 38232 was probably presynaptic in origin since it was associated with a significant reduction in paired-pulse ratio. In addition, in patch clamp experiments, S 38232 enhanced the frequency (but not the amplitude) of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs, sIPSCs) recorded from CA1 principal cells. Moreover, it enhanced the frequency of miniature IPSCs but not EPSCs, suggesting that it was acting on nAChRs located on presynaptic/pre-terminal regions of GABAergic interneurons. The effect of S 38232 on GABAergic signaling was concentration-dependent with an EC(50) of 43muM. In conclusions, we present evidence that the new nicotine ligand S 38232, by selectively activating non-alpha7 nAChRs located on principal cells and GABAergic interneurons, influences network activity and information processing in the hippocampus.
细胞外场电位 (fEPSPs) 和全细胞膜片钳记录用于测试新型强效非-α7 烟碱型乙酰胆碱受体 (nAChR) 激动剂 S 38232 对成年小鼠海马切片突触传递的影响。S 38232 增加了由 Schaffer 侧支刺激在放射层中诱发的 fEPSPs 的幅度。这种作用被 picrotoxin 增强，表明 S 38232 至少部分作用于 GABA 能中间神经元。S 38232 的作用是通过非-α7 包含的 nAChR 介导的，因为它被 DHbetaE(1μM) 而不是 α-BTX(100nM) 阻止。当在 picrotoxin 存在下将尼古丁 (1μM) 应用于来自 α7-/- 小鼠的海马切片时，观察到对 fEPSPs 的类似增强作用。S 38232 的增强作用可能源于突触前，因为它与配对脉冲比的显著降低有关。此外，在膜片钳实验中，S 38232 增强了从 CA1 主细胞记录的自发兴奋性和抑制性突触后电流 (sEPSC、sIPSC) 的频率(但不包括幅度)。此外，它增强了微小 IPSC 的频率但不增强 EPSC 的频率，表明它作用于位于 GABA 能中间神经元的突触前/前末端区域的 nAChR。S 38232 对 GABA 能信号传递的作用具有浓度依赖性，EC50 为 43μM。总之，我们提供的证据表明，新型尼古丁配体 S 38232 通过选择性激活位于主细胞和 GABA 能中间神经元上的非-α7 nAChR，影响海马体中的网络活动和信息处理。
