DataSheet1_Adar3 Is Involved in Learning and Memory in Mice.DOCX

The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala, and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl-mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals.

基因组中编码的调控RNA的数量以及通过腺苷脱氨酶将腺苷转化为肌苷（A-I）的转录后去氨化修饰的程度随着发育复杂性的增加而增加，这可能是动物认知进化的一个重要因素。ADAR蛋白家族中A-I编辑的最新成员，特异于脊椎动物的ADAR3，在大脑中高表达，但其功能意义尚不清楚。体外研究提示ADAR3作为A-I RNA编辑的负调节因子发挥作用，但其作用范围和潜在机制尚不明确。对已发表数据的元分析表明，小鼠Adar3的表达在 hippocampus（海马体）、thalamus（丘脑）、amygdala（杏仁核）和olfactory region（嗅球）中最高。与这一发现一致，我们观察到缺乏Adar3的第3外显子（编码两个双链RNA结合域）的 mice（小鼠）焦虑水平升高，以及海马体依赖的短期和长期记忆形成缺陷。RNA测序揭示了Adar3缺陷小鼠海马体中参与突触功能基因的失调。我们还发现，在KCl介导的激活过程中，ADAR3从细胞质短暂转移到细胞核。这些结果表明，ADAR3在哺乳动物的认知过程中发挥作用。