M1毒蕈碱型胆碱受体(M1受体)在学习记忆等活动中作用显著。研究表明M1受体可直接或通过增强NMDA受体的功能影响海马神经元的突触可塑性，但对AMPA受体的影响尚未完全阐明，而AMPA受体在神经元内的运输对突触功能起关键作用。前期研究我们证明M1受体激动有助于海马神经元中的GluA1向突触后致密区分泌；同时发现神经元表面GluA2的数量与磷酸化水平亦受其影响。因此我们拟通过活细胞动态观察、突触后致密物蛋白提取等方法深入研究M1受体对AMPA受体GluA2运输的调控作用及其机制；应用点突变小鼠海马脑片研究GluA2的运输在M1受体调控突触可塑性中的作用；应用整体动物模型解析该作用在M1受体调控整体学习记忆中的影响。本课题有助于进一步揭示M1受体激动促进学习记忆的分子机制，有望在阿尔茨海默病等认知功能障碍疾病防治的基础研究中获得新突破。

M1 Muscarinic acetylcholine receptor plays an important role in learning and memory. Activation of M1 receptor modulates synaptic plasticity of hippocampal neurons directly or by enhancing the function of NMDA receptors. AMPA receptor trafficking plays a key role in the regulation of the synaptic strength. However, the regulation of AMPA receptor by muscarinic receptors has not been fully clarified. In our preliminary study, we demonstrated that activation of M1 receptor could modulate the trafficking of GluA1 subunits of AMPA receptors in cells of cultured primary hippocampal neurons, which contributes to the secretion of GluA1 to the postsynaptic density.Meanwhile we found that the number and phosphorylation level of GluA2 on the surface of neurons were modulated by M1 receptors as well. The research results of GluA2 help to clarify the modulation mechanism and significance of AMPA receptors by M1 receptors, therefore we will further clarify the details of the regulation of GluA2 trafficking by activation of M1 receptor and elucidate the underlying mechanism through live cell imaging andsubcellular fractionation of postsynaptic densities. Moreover, we will investigate the role of such regulation in synaptic plasticity in hippocampal slices from the mutant mice lack of the phosphorylation sites of GluA2 and in learning and memory in memory-impaired and Alzheimer’s disease mouse models and the phosphomutant mice of GluA2. The study will provide new insight in the role of M1 receptor in enhancement of cognition and it may give a chance to the development of novel methods to combat the impairment of cognitive function such as in Alzheimer’s disease.