Department of Neuroscience, College of Medicine, University of Florida,1600 S.W. Archer Road, Gainesville, FL 32610, USA.
J Physiol. 2010 Aug 1;588(Pt 15):2801-22. doi: 10.1113/jphysiol.2009.184648. Epub 2010 Jun 14.
We report that bath application of 3 mum carbachol (CCh), a muscarinic acetylcholine receptor agonist, reduces evoked IPSC amplitude recorded from hilar mossy cells in the rat dentate gyrus through a presynaptic mechanism. While CCh has been shown to inhibit evoked IPSCs in other systems, this effect is intriguing in that it does not require inhibitory action of either presynaptic muscarinic receptors or presynaptic cannabinoid receptors. Previous work from our lab has shown that identical application of CCh produces an action potential-dependent increase in ambient GABA in this system; however, inhibition of evoked IPSCs produced by both 3 and 10 mum CCh is insensitive to the GABA(B) antagonist CGP52432. Therefore we hypothesized that CCh-mediated inhibition of evoked IPSCs might be produced by activity-dependent increases in ambient GABA and subsequent activation of presynaptic GABA(A) receptors. Consistent with that hypothesis, we report that CCh-mediated inhibition of evoked IPSCs appears to be well correlated with CCh-mediated facilitation of spontaneous IPSCs and that CCh does not affect GABA(B)-mediated IPSCs recorded in the presence of the GABA(A) receptor antagonist picrotoxin. Intriguingly, however, we found that bath application of the GAT-1 transport blocker NO-711 (1 mum) produces inhibition of evoked IPSCs that is reversed by CGP52432, and that lower doses of CCh produce inhibition with greater CGP52432 sensitivity. These observations, combined with subsequent work on multiple pulse depression, reveal that feedback inhibition of GABAergic afferents to hilar mossy cells is governed by a complex relationship between two distinct and activity-dependent mechanisms.
我们报告说，3 mum 乙酰胆碱（CCh）的浴应用，一种毒蕈碱乙酰胆碱受体激动剂，通过突触前机制减少大鼠齿状回颗粒细胞中记录到的诱发 IPSC 幅度。虽然 CCh 已被证明在其他系统中抑制诱发 IPSC，但这种效应很有趣，因为它不需要突触前毒蕈碱受体或突触前大麻素受体的抑制作用。我们实验室的先前工作表明，相同的 CCh 应用会导致该系统中环境 GABA 的动作电位依赖性增加；然而，3 和 10 mum CCh 产生的诱发 IPSC 抑制对 GABA(B)拮抗剂 CGP52432 不敏感。因此，我们假设 CCh 介导的诱发 IPSC 抑制可能是由环境 GABA 的活性依赖性增加和随后的突触前 GABA(A)受体激活产生的。与该假说一致，我们报告说，CCh 介导的诱发 IPSC 抑制似乎与 CCh 介导的自发 IPSC 易化密切相关，并且 CCh 不影响在 GABA(A)受体拮抗剂 picrotoxin 存在下记录的 GABA(B)介导的 IPSC。然而，有趣的是，我们发现，GAT-1 转运阻滞剂 NO-711（1 mum）的浴应用会产生诱发 IPSC 的抑制，这种抑制可被 CGP52432 逆转，并且较低剂量的 CCh 产生抑制作用时对 CGP52432 的敏感性更高。这些观察结果，加上随后对多脉冲抑制的研究，揭示了 GABA 能传入到颗粒细胞的反馈抑制受两种不同且依赖于活性的机制之间的复杂关系支配。
