Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.
Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.
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DOI：
10.1093/cercor/bhv227
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Mellor JR
中科院分区：
文献类型：
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作者：
Dennis SH;Pasqui F;Colvin EM;Sanger H;Mogg AJ;Felder CC;Broad LM;Fitzjohn SM;Isaac JT;Mellor JR
毒蕈碱M1乙酰胆碱受体（M1Rs）在海马体中高度表达，其抑制或消融会破坏空间记忆的编码。据推测，M1Rs影响空间记忆的主要机制是通过调节海马突触可塑性。在这里，我们使用了最近开发的，具有良好特征的选择性M1R激动剂和M1R敲除小鼠的组合来确定M1Rs在海马神经元和突触功能调节中的作用。我们证实M1R激活增加了输入阻力和海马CA1锥体神经元的去极化，并表明这大大增加了兴奋性突触后电位-尖峰耦合。与M1R在突触可塑性中的关键作用一致，我们现在表明M1R激活产生谷氨酸能突触传递到CA1锥体神经元的强大增强，具有长期增强（LTP）的所有特征：增强需要NMDA受体活性，并且与突触诱导的LTP双向阻断。因此，我们描述了乙酰胆碱通过M1Rs激活CA1锥体神经元并诱导LTP的协同机制，从而深刻地增加CA1锥体神经元的激活。这些特征被预测为胆碱能在啮齿动物和人类中传播的促认知作用的主要贡献。
Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans.