Medical Research Council Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Neuron. 2010 Dec 9;68(5):948-63. doi: 10.1016/j.neuron.2010.11.018.
Muscarinic receptor activation facilitates the induction of synaptic plasticity and enhances cognitive function. However, the specific muscarinic receptor subtype involved and the critical intracellular signaling pathways engaged have remained controversial. Here, we show that the recently discovered highly selective allosteric M(1) receptor agonist 77-LH-28-1 facilitates long-term potentiation (LTP) induced by theta burst stimulation at Schaffer collateral synapses in the hippocampus. Similarly, release of acetylcholine by stimulation of cholinergic fibers facilitates LTP via activation of M(1) receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M(1) receptor activation, indicating this is the mechanism for LTP facilitation. M(1) receptors were found to enhance NMDAR activation by inhibiting SK channels that otherwise act to hyperpolarize postsynaptic spines and inhibit NMDAR opening. Thus, we describe a mechanism where M(1) receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus.
毒蕈碱型乙酰胆碱受体激活促进突触可塑性诱导和增强认知功能。然而，涉及的特定毒蕈碱型乙酰胆碱受体亚型和涉及的关键细胞内信号通路仍存在争议。在这里，我们表明，最近发现的高度选择性变构 M1 受体激动剂 77-LH-28-1 促进海马体 Schaffer 侧枝突触的θ爆发刺激诱导的长时程增强（LTP）。同样，通过刺激胆碱能纤维释放乙酰胆碱通过激活 M1 受体促进 LTP。在θ爆发刺激期间 N-甲基-D-天冬氨酸受体（NMDAR）的开放通过 M1 受体的激活得到增强，表明这是 LTP 促进的机制。发现 M1 受体通过抑制 SK 通道来增强 NMDAR 的激活，否则 SK 通道会使突触后棘去极化并抑制 NMDAR 的开放。因此，我们描述了一种机制，其中 M1 受体激活抑制 SK 通道，允许增强的 NMDAR 活性，并导致海马体中 LTP 诱导的易化。
