脆性X综合症（FXS）是由Fmr1基因甲基化静默导致的遗传性智力发育迟滞精神疾病，如何有效改善FXS病理症状目前仍是一个难题。本项目采用神经电生理、生物化学和药理学等方法，对Fmr1编码蛋白FMRP及其下游蛋白APP的信号通路如何调控海马突触可塑性进行研究，尤其关注APP裂解产物Aβ在FXS突触可塑性损伤中的作用。我们认为，Fmr1 KO小鼠脑内Aβ的增加是造成LTP和LTD异常的危险因素，BAX-Caspase 3-Akt-GSK3信号通路的激活是Aβ损伤Fmr1 KO小鼠海马LTP的分子机制；Fmr1 KO小鼠海马异常增强的mGluR-LTD可能与Aβ介导的AMPA受体内吞作用增加有关。我们将对这些假设进行验证，在此基础上，通过药物干预APP-GSK3信号通路，以改善Fmr1 KO小鼠突触可塑性和学习记忆。本项目的开展，有助于更深入地了解FXS的病理机制，为筛选特异性药物靶点提供依据。

Fragile X Syndrome (FXS), caused by the silence of Fmr1 gene, is an inherited disease with mental retardation. How to effectively remedy and relieve pathogenic symptoms of FXS remains an unsolved problem. In our proposal, we will first explore how the signaling pathway of FMRP, which is encoded by Fmr1 gene, and its downstream APP regulate hippocampal synaptic functions by using electrophysiological, biochemical, and pharmacological techniques. We will especially focus on Aβ which is the cleaved product of APP for its role in the regulation of hippocampal synaptic plasticity in FXS. We suppose that the increase of Aβ in the brain of Fmr1 KO mice leads to abnormal LTP and LTD in hippocampus. Aβ-mediated activation of BAX-Caspase 3-Akt-GSK3 signaling pathway might be the critical event related with hippocampal LTP impairment. Moreover, the abnormally enhanced mGluR-dependent LTD in hippocampus of Fmr1 KO mice might be related with Aβ-mediated increase of AMPA receptor endocytosis. We will verify these hypotheses in this proposal, and then take efforts to improve synaptic plasticity and learning and memory in Fmr1 KO mice through the way of drug interventions on APP-GSK3 signaling pathway. Our proposal will provide a chance for a deeper understanding about pathogenic mechanism of FXS, and for the development of therapeutic drugs with specific molecular targets at FXS.