脆性X综合症为临床常见的遗传性智力低下症，探索其发病机制及药物治疗途径是社会和临床急需解决的一个重要课题。我们前期研究采用脆性X综合症动物模型FMR1基因敲除小鼠，发现皮层神经元树突发育和突触形成均出现障碍，而原因之一是由星形胶质细胞来源的神经营养因子-3（NT-3）分泌过多；高浓度的NT-3诱导氧化应激损伤可能是引起树突与突触发育障碍的主要原因。然而，FMR1基因功能缺失是如何引起NT-3分泌增加，过高的NT-3又是如何引起神经元发育障碍的分子机制仍不清楚。本项目以FMR1基因敲除小鼠为研究模型，从NT-3分泌异常入手，利用电生理、分子生物学、药理学和行为学等手段，首次探索NT-3与脆性X综合症病理机制的关系，以期阐明脆性X综合症NT-3调节神经元发育异常的分子机制。本研究对深入了解脆性X综合症的病理机制，发掘潜在的药物治疗新靶点具有重要意义，可望为临床治疗提供新的思路和理论依据。

Fragile X syndrome is a common clinical genetic mental retardation disorder. Exploration of the pathogenesis and drug therapy is an important topic to be resolved. Our previous studies using the FMR1 gene knockout mice, a models of fragile X syndrome, found that excessive secretion of the astrocyte-derived neurotrophic factor-3 (NT-3) caused the abnormal cortical neurons dendritic development and synapse formation. The major reason might be that oxidative stress induced by high concentrations of NT-3 from astrocytes caused the dendritic and synaptic development disorder. However, the mechanisms are still unclear that lack of the FMR1 gene function leads to the increase of NT-3 secretion and high level of NT-3 causes neuronal developmental disorders. The present project aims to explore pathological mechanisms of excessive NT-3 underlying neuronal developmental disorders in the animal model of Fragile X syndrome by electrophysiological, molecular biological, pharmacological, and behavioral methods. It is the first time to clarify the molecular mechanisms of NT-3 regulating neuronal development of the Fragile X syndrome. It will be helpful to get insight into the pathological mechanisms of Fragile X syndrome and provide potential target and theoretical basis for the clinical treatment.