M1 muscarinic receptors facilitate hippocampus-dependent cognitive flexibility via modulating GluA2 subunit of AMPA receptors
M1 muscarinic receptors facilitate hippocampus-dependent cognitive flexibility via modulating GluA2 subunit of AMPA receptors
复制标题
M1 毒蕈碱受体通过调节 AMPA 受体的 GluA2 亚基来促进海马依赖性认知灵活性。
DOI：
10.1016/j.neuropharm.2018.12.005
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发表时间：
2019
影响因子：
4.7
通讯作者：
Qiu Yu
中科院分区：
文献类型：
--
作者：
Xiong Cai-Hong;Liu Ming-Gang;Zhao Lan-Xue;Chen Mu-Wen;Tang Ling;Yan Ying-Hui;Chen Hong-Zhuan;Qiu Yu
认知灵活性是执行功能的一个重要方面。胆碱能系统是认知的重要组成部分，主要通过纹状体和前额皮质调节认知灵活性。M1毒蕈碱受体（M1 mAChRs）是胆碱能系统中一个重要的治疗靶点，其在海马依赖性认知灵活性中的作用尚不清楚。在本研究中，我们证明了M1 machr的选择性激活促进了Morris水迷宫中初始学习反应的消退，并促进了逆转学习的习得，这是一种主要依赖于海马的行为测试。然而，在蛋白激酶C （PKC）磷酸化Ser880缺失的GluA2突变小鼠中，这些作用被消除。M1 mAChR激活诱导的海马CA1区进一步长期抑郁（LTD）依赖于AMPA受体亚基GluA2，而不依赖于GluA1。M1 mAChRs通过PKC磷酸化Ser880增加GluA2的内吞作用。PKC的抑制阻断了M1 machr介导的LTD、记忆转换和逆向学习促进。此外，在GluA2突变小鼠和PKC抑制剂处理的小鼠中观察到的缓慢记忆消退似乎影响了逆转学习的巩固和检索。因此，这些结果表明M1 machr主要促进空间反转学习中的习得，并进一步阐明这种作用依赖于PKC对GluA2的磷酸化。该研究有助于阐明M1 machr在认知灵活性中的作用，并可能促进认知不灵活性的早期预防。
Cognitive flexibility is an important aspect of executive function. The cholinergic system, an important component of cognition, has been shown to modulate cognitive flexibility mainly through the striatum and prefrontal cortex. The role of M1 muscarinic receptors (M1 mAChRs), an important therapeutic target in the cholinergic system, in hippocampus-dependent cognitive flexibility is unclarified. In the present study, we demonstrated that selective activation of M1 mAChRs promoted extinction of initial learned response and facilitated acquisition of reversal learning in the Morris water maze, a behavior test that is mainly dependent on the hippocampus. However, these effects were abolished in GluA2 mutant mice with deficiency in phosphorylation of Ser880 by protein kinase C (PKC). Further long-term depression (LTD) in the hippocampal CA1 area induced by M1 mAChR activation was shown to be dependent on AMPA receptor subunit GluA2 but not GluA1. M1 mAChRs increased GluA2 endocytosis through phosphorylation of Ser880 by PKC. Inhibition of PKC blocked M1 mAChR-mediated LTD, memory switching and reversal learning facilitation. Moreover, the slow memory extinction observed in GluA2 mutant mice and PKC inhibitor-treated mice appeared to affect the consolidation and retrieval of reversal learning. Thus, these results demonstrate that M1 mAChRs mainly facilitate acquisition in spatial reversal learning and further elucidate that such an effect is dependent on the phosphorylation of GluA2 by PKC. The study helps clarify the role of M1 mAChRs in cognitive flexibility and may prompt the earlier prevention of cognitive inflexibility.