特异性敲除梨状皮层锥体神经元Fmr1基因对嗅觉功能的影响及机制研究

Fmr1基因突变是常见的自闭症单基因致病因素。全身敲除Fmr1基因的自闭症模型小鼠与自闭症患者一样都表现出明显的嗅觉障碍，但其内在机制不清楚。梨状皮层是嗅觉的重要高级中枢，在气味信息的表征过程中起关键作用，且申请者最近的研究表明特异性敲除梨状皮层锥体神经元的Fmr1基因会影响小鼠的气味分辨能力，提示梨状皮层锥体神经元Fmr1表达异常与自闭症嗅觉障碍有关。本项目拟在小鼠梨状皮层锥体神经元特异性敲除Fmr1，在明确该基因在锥体神经元缺失会影响小鼠嗅觉功能的基础上，应用形态学手段、在体电生理记录、光纤钙记录等方法研究Fmr1特异性敲除对神经元形态以及电生理特性的影响，并进一步应用转录组测序筛选出Fmr1敲除引起的差异表达蛋白，以及采用脑片膜片钳和药理学方法探讨特异性敲除Fmr1基因对嗅觉功能影响的具体机制。研究结果将有利于揭示自闭症嗅觉障碍的机制，为自闭症的防治提供新的线索。

Mutations in the Fmr1 gene are the leading monogenic causes of Autism spectrum disorders (ASD). Fmr1 knockout mice exhibit abnormal olfactory function as in individuals with ASD. However, the specific mechanism about olfactory disability of ASD is still unclear. The piriform cortex is a key olfactory center which plays important role in representation of odor information. Our recent research showed that Fmr1 gene deficiency in pyramidal neurons of piriform cortex decreased the ability of odor discrimination of mice, indicating that the abnormal expression of Fmr1 in pyramidal neurons of piriform cortex is involved in the olfactory disorders in autism. This project will specifically knockout Fmr1 gene in pyramidal neurons in piriform cortex and use behavioral experiments to confirm the effect of Fmr1 deletion on olfactory function. And on this basis, morphology research, in vivo electrophysiological recordings and fiber photometry technique will be used to study the neuronal morphology and electrophysiological properties. Further, we will apply RNA-Seq to find out the proteins regulated by Fmr1 knockout, then use patch-clamp system combined with pharmacological study to reveal the mechanism of olfactory disorders caused by Fmr1 deficiency. The results will help to recover the reason of olfactory dysfunction in ASD and provide new clues on the therapy of autism.