唐氏综合征（Down syndrome，DS）是导致人类先天性认知功能障碍最常见的原因，但其机制尚未完全阐明。本课题组利用生物信息学软件分析发现，人类21号染色体转录的miR-99a可结合在腺苷酸环化酶1（AC1） mRNA的3'端非翻译区。已知AC1及其下游信号通路在认知功能调节中发挥关键作用，且我们的前期研究发现在神经元中过表达miR-99a可显著抑制AC1 mRNA和蛋白表达，然而miR-99a是否通过调控AC1信号通路在DS认知功能障碍中发挥关键作用尚未可知。在前期研究基础上，本项目拟首先阐明miR-99a是否可以调控AC1的表达；然后利用DS小鼠模型明确miR-99a/AC1对神经元内在可塑性和突触可塑性的调控作用；最后探讨miR-99a/AC1在DS认知功能障碍中的作用机制。总之，本项目期望系统揭示miR-99a/AC1在DS发病机理中的作用及其机制，以探索干预DS的新靶标。

Down syndrome or Down's syndrome （DS）, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. DS is the most common chromosome abnormality in humans, occurring in about 1 per 1000 babies born each year. However, the molecular mechanisms of cognitive deficits of DS are still unknown. We found that miR-99a might bind to the 3` untranslated region of adenylyl cyclase 1 （AC1） using bioinformatics softwares. We also found that overexpression of miR-99a decreased the expression of AC1 at the mRNA and protein levels as detected by quantitative RT-PCR and Western Blot in cultured primary neurons.It has been reported that AC1 and its down stream signals play an important role in learning and memory. However, the role of miR-99a in regulating AC1, in synaptic and intrinsic plasticity,and in learning and memory is still unknown and need to be explored. Therefore, we hypothesize that miR-99a plays a vital role in cognitive deficits in DS by regulating AC1. In the present study, we will first explore whether miR-99a regulates AC1 based on our previous research. Then the role of miR-99a in synaptic and intrinsic plasticity, and in learning and memory will be detected. At last, whether miR-99a exerts its function in DS cognitive deficits through regulating AC1 will be determined. Taken together, this projects aims to elucidate the precise role of miR-99a/AC1 in memory and in DS cognitive defictis. These findings will provide novel evidence for the development of new therapeutic strategies to treat DS.