M1胆碱受体对AMPA受体GluA1亚基的调控及其在突触长时程增强和学习记忆中的作用及机制

项目名称： M1胆碱受体对AMPA受体GluA1亚基的调控及其在突触长时程增强和学习记忆中的作用及机制

项目编号： No.81473217

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邱瑜

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： 学习记忆等高级认知活动是神经递质、受体之间精细、复杂的调控结果。大量研究表明M1胆碱受体与离子型谷氨酸受体AMPA受体都对突触长时程增强（LTP）和学习记忆有密切关系，然而两者之间的相互调控尚未明了。并且M1受体激动剂被认为是治疗阿尔茨海默病（AD）的有效药物，但AD患者脑内AMPA受体下调。因此有必要深入研究M1受体对AMPA受体的调控作用，将有助于阐明学习记忆的生理机制，并进一步探明M1受体激动剂治疗AD的有效性。我们前期研究发现激动M1受体增加AMPA受体GluA1亚基在海马神经元表面的数量并增加其磷酸化程度。本课题拟深入研究M1受体调控GluA1亚基的作用及机制；研究该作用在M1受体增强LTP和整体学习记忆中的作用；明确AD病理情况下M1受体对GluA1亚基的调控及其在M1受体增强LTP和学习记忆中的作用。本课题是对M1受体调控学习记忆作用机制的新探索，并可能为AD治疗提供新思路。

中文关键词： 阿尔茨海默病；M1毒蕈碱型胆碱受体；AMPA受体；长时程增强；学习记忆

英文摘要： The accurate and complex interactions between neurotransmitters and receptors form the mechanistic bases for learning and memory. It has been widely demonstrated that both M1 muscarinic acetylcholine receptor and AMPA receptor (an ionotropic glutamate receptor) play important roles in the regulation of the synaptic strength and learning and memory. However, the relationship between them has not been fully clarified. Moreover, M1 agonists are considered to be potential treatment for Alzheimer's disease (AD). However, AMPA receptor has been reported to be reduced in AD brains. Therefore, it is necessary to explore the modulation of AMPA receptor by M1 receptor, in order to further elucidate the molecular mechanisms of synaptic plasticity and cognitive function and to examine the efficiency of M1 agonist in the treatment of AD. In our preliminary study, we demonstrated that activation of M1 receptor could increase the number of GluA1 subunit of AMPA receptor on cell surface of cultured primary hippocampal neurons. Further, activation of M1 receptor modulated the phosphorylation of GluA1, which has been shown to be critical for the function of the receptor. Based on our preliminary results, we will study the details of the modulation of GluA1 by activation of M1 receptor and the underlying mechanism through live cell imaging, immunoflurescence of postsynaptic densities and site-directed mutagenesis. We will investigate the role of such modulation in long-term potentiation and in learning and memory by employing the phosphomutant mice of GluA1. Furthermore, we will investigate the regulation of GluA1 by M1 recptor in AD animal models and elucidate its role in synaptic plasticity and learning and memory in AD. The study may provide new insights of the mechanisms underlying function of M1 receptor and it may give a chance to the development of novel methods to combat the impairment of cognitive function in Alzheimer's disease.

英文关键词： Alzheimer's disease;M1 Muscarinic receptor;AMPA receptor;Long-term potentiation;Learning and memory