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首页> 外文期刊>The European Journal of Neuroscience >Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus.
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Postsynaptic M1 and M3 receptors are responsible for the muscarinic enhancement of retrograde endocannabinoid signalling in the hippocampus.

机译：突触后M1和M3受体负责海马体内逆行内源性大麻素信号传导的毒蕈碱增强。

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摘要

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 microM 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 M1-knockout and M3-knockout mice, but was virtually eliminated in the neurons from M1/M3-compound-knockout mice. CCh still enhanced DSI significantly under the blockade of postsynatpic K(+) conductance, and did not significantly influence the depolarization-induced Ca(2+) transients. These results indicate that the activation of postsynaptic M1 and M3 receptors facilitates the depolarization-induced release of endocannabinoids.
机译：胆碱能系统对于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（mAChRs）介导，该受体由五个亚型（M（1）-M（5））组成。最近的研究表明乙酰胆碱作为内源性大麻素信号的有效增强剂的新作用，该信号从突触后到突触前神经元逆行。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全细胞配对记录，并监测了抑制性突触后电流（IPSC）。突触后去极化诱导IPSCs（DSI）的瞬时抑制，这种现象已知涉及内源性大麻素的逆行信号传导。胆碱能激动剂卡巴胆碱（CCh）在0.01-0.3 microM时可显着增强DSI，而不会改变突触前大麻素的敏感性。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。它也被不可水解的GDP类似物（GDP-β-S）阻断，该类似物在细胞内应用于突触后神经元。 DSI的毒蕈碱增强作用在从M1敲除和M3敲除小鼠制备的神经元中一直持续存在，但在M1 / M3化合物敲除小鼠的神经元中却几乎消除。 CCh仍然在突触后K（+）电导的阻滞下显着增强DSI，并且没有显着影响去极化诱导的Ca（2+）瞬变。这些结果表明，突触后M1和M3受体的激活促进去极化诱导的内源性大麻素释放。

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