Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus
Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus
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DOI：
10.1046/j.1460-9568.2003.02732.x
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发表时间：
2003-07-01
影响因子：
3.4
通讯作者：
Kano, M
中科院分区：
文献类型：
--
作者：
Ohno-Shosaku, T;Matsui, M;Kano, M
胆碱能系统对包括学习和记忆在内的高级大脑功能至关重要。这些功能主要由毒蕈碱乙酰胆碱受体（machr）介导，machr由5个亚型（M-1-M-5）组成。最近的一项研究表明，乙酰胆碱作为内源性大麻素信号的有效增强剂，从突触后神经元向突触前神经元逆行作用。在本研究中，我们进一步研究了这种胆碱能作用对内源性大麻素信号传导的机制。我们对培养的海马神经元进行了成对的全细胞记录，并监测了抑制性突触后电流（IPSCs）。突触后去极化诱导了IPSCs （DSI）的短暂抑制，这一现象已知涉及内源性大麻素的逆行信号传导。胆碱能激动剂carbachol （CCh）在0.01 ~ 0.3 ma时显著提高DSI，但未改变突触前大麻素敏感性。毒蕈碱激动剂oxotremorine-M可模拟CCh对DSI的促进作用，而毒蕈碱拮抗剂阿托品可消除CCh对DSI的促进作用。它也被一种不可水解的GDP类似物（GDP- β - s）阻断，这种类似物应用于细胞内的突触后神经元。在M-1敲除和M-3敲除小鼠制备的神经元中，毒蕈碱对DSI的增强在很大程度上持续存在，但在M-1/M-3化合物敲除小鼠制备的神经元中几乎被消除。在突触后K+电导阻断的情况下，CCh仍能显著增强DSI，但对去极化诱导的Ca2+瞬态没有显著影响。这些结果表明突触后M-1和M-3受体的激活促进了去极化诱导的内源性大麻素的释放。
The cholinergic system is crucial for higher brain functions including learning and memory. These functions are mediated primarily by muscarinic acetylcholine receptors (mAChRs) that consist of five subtypes (M-1-M-5). A recent study suggested a novel role of acetylcholine as a potent enhancer of endocannabinoid signalling that acts retrogradely from postsynaptic to presynaptic neurons. In the present study, we further investigated the mechanisms of this cholinergic effect on endocannabinoid signalling. We made paired whole-cell recordings from cultured hippocampal neurons, and monitored inhibitory postsynaptic currents (IPSCs). The postsynaptic depolarization induced a transient suppression of IPSCs (DSI), a phenomenon known to involve retrograde signalling by endocannabinoids. The cholinergic agonist carbachol (CCh) markedly enhanced DSI at 0.01-0.3 mum without changing the presynaptic cannabinoid sensitivity. The facilitating effect of CCh on DSI was mimicked by the muscarinic agonist oxotremorine-M, whereas it was eliminated by the muscarinic antagonist atropine. It was also blocked by a non-hydrolizable analogue of GDP (GDP-beta-S) that was applied intracellularly to postsynaptic neurons. The muscarinic enhancement of DSI persisted to a substantial degree in the neurons prepared from M-1-knockout and M-3 -knockout mice, but was virtually eliminated in the neurons from M-1/M-3-compound-knockout mice. CCh still enhanced DSI significantly under the blockade of postsynatpic K+ conductance, and did not significantly influence the depolarization-induced Ca2+ transients. These results indicate that the activation of postsynaptic M-1 and M-3 receptors facilitates the depolarization-induced release of endocannabinoids.