Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells
Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells
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DOI：
10.1073/pnas.95.19.11465
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发表时间：
1998-09-15
影响因子：
11.1
通讯作者：
Conn, PJ
中科院分区：
文献类型：
--
作者：
Marino, MJ;Rouse, ST;Conn, PJ
有证据表明，海马体的胆碱能输入在学习和记忆中起重要作用，海马体胆碱能末端的退化可能导致与阿尔茨海默病相关的记忆丧失。胆碱能激动剂对海马生理的一个更突出的作用是毒蕈碱受体激动剂对n -甲基- d -天冬氨酸（NMDA）受体电流的增强。在这里，我们使用传统的药理学试剂和ml-毒素，一种具有前所未有选择性的mi拮抗剂，来证明海马CA1锥体细胞中NMDA受体电流的增强是由基因定义的mi毒蕈碱受体介导的。此外，我们在电子显微镜水平上证明了mi毒蕈碱受体和NR1a NMDA受体亚基的共定位，表明了这两个受体之间的空间关系，这将允许这两个受体之间的生理相互作用。它对学习和记忆的研究以及治疗神经退行性疾病（如阿尔茨海默氏症）的药物设计具有重要意义。
Evidence suggests that cholinergic input to the hippocampus plays an important role in learning and memory and that degeneration of cholinergic terminals in the hippocampus may contribute to the memory loss associated with Alzheimer's disease. One of the more prominent effects of cholinergic agonists on hippocampal physiology is the potentiation of N-methyl-D-aspartate (NMDA)-receptor currents by muscarinic agonists, Here, we employ traditional pharmacological reagents as well as ml-toxin, an mi antagonist with unprecedented selectivity, to demonstrate that this potentiation of NMDA-receptor currents in hippocampal CA1 pyramidal cells is mediated by the genetically defined mi muscarinic receptor. Furthermore, we demonstrate the colocalization of the mi muscarinic receptor and the NR1a NMDA receptor subunit at the electron microscopic level, indicating a spatial relationship that would allow for physiological interactions between these two receptors, This work demonstrates that the ml-muscarinic receptor gene product modulates excitatory synaptic transmission, and it has important implications in the study of learning and memory as well as the design of drugs to treat neurodegenerative diseases such as Alzheimer's.