miR-384-5p在注意缺陷多动障碍学习记忆损伤中的作用与机制研究

ADHD is always accompanied by learning and memory impairment and its mechanism is still unknown. miR-384-5p is a significantly down-regulated miRNA expressed in the hippocampus of SHR. We found that after the silence of miR-384-5p expression of hippocampus, the rats show the impairmant of learning and memory. Bioinformatics prediction and experimental result confirmed CDH13 as the target genes of miR-384-5p. As a kind of T-cadherin, CDH13 plays an important role in synaptic plasticity and learning and memory,which means miR-384-5p could lead to learning and memory impairment through decreasing CDH13. This study is to observe evidences of learning and memory impairment by examin the expression miR-384-5p in vivo, and overexpression or silencing of miR-384-5p in vitro. We overexpression or silencing the CDH13 gene in the primary cultured hippocampal neurons, further with the CDH13 mechanism of miR-384-5p on synaptic plasticity will be investigated. We evaluate the universality of “miR-384-5p-CDH13” in different ADHD animal models. The resaerch on miR-384-5p provide us a new target of the treatment of ADHD.

注意缺陷多动障碍（ADHD）是一种伴有学习记忆损伤的神经行为障碍，发病机制未明。miR-384-5p是我们应用芯片技术获得的、在SHR大鼠海马组织中显著低表达的microRNA。前期发现，大鼠海马组织中沉默miR-384-5p表达可出现学习记忆损伤；软件分析和实验均证实CDH13为miR-384-5p潜在靶标，已知CDH13可调节突触可塑性、参与学习记忆损伤；提示miR-384-5p可调控CDH13表达参与ADHD发生。本课题通过检测miR-384-5p在ADHD临床血液样本、ADHD动物模型药物治疗前后表达，进一步评估miR-384-5p与ADHD关系；在体水平采用过表达、沉默技术，获得miR-384-5p参与学习记忆损伤的证据；以原代培养海马神经元为工具，以CDH13为机制研究切入点，论证miR-384-5p参与ADHD学习记忆损伤的分子机制。本研究有望为ADHD的防治提供新干预靶标。

注意缺陷多动障碍(ADHD)是一种常见的神经精神疾病，以注意力不集中、多动、冲动为特征，伴有学习和记忆缺陷。目前很少有研究探讨mirna在多动症认知功能障碍中的作用。本研究在广泛使用的ADHD模型中研究了miR-384-5p表达对学习和记忆的影响。将慢病毒载体注入大鼠侧脑室，沉默或过表达miR-384-5p水平。为了确定异常的miR-384-5p表达是否影响学习和记忆，通过开场试验和Morris水迷宫测试评估了自发活动和认知功能。在Morris水迷宫实验的位置巡航实验中，过表达miR-384-5p的大鼠较对照组明显缩短了到达平台的时间和总游泳距离，而miR-384-5p沉默组则与之相反。过表达或抑制miR-384-5p后脑组织病理学形态无明显变化;然而，多巴胺(DA)受体(DR)D1水平在前额叶皮层(PFC)中分别降低和升高。野生型DRD1组荧光素酶活性降低。miR-384-5p过表达可使SHR大鼠PFC中环状AMP反应元件结合蛋白(CREB)磷酸化水平升高，DA转运蛋白(DAT)水平降低。此外，与对照组相比，miR-384-5p的抑制增加了DRD1，降低了DAT和CREB蛋白水平。这些发现提示miR-384-5p可能在ADHD的学习和记忆障碍中发挥关键作用。