Iwata Ryohei, Ohi Kazutaka, Kobayashi Yuki, Masuda Akira, Iwama Mizuho, Yasuda Yuka, Yamamori Hidenaga, Tanaka Mika, Hashimoto Ryota, Itohara Shigeyoshi, Iwasato Takuji
Division of Neurogenetics, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan; Department of Genetics, The Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka 411-8540, Japan.
Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Cell Rep. 2014 Sep 11;8(5):1257-64. doi: 10.1016/j.celrep.2014.07.047. Epub 2014 Aug 21.
A major concern in neuroscience is how cognitive ability in adulthood is affected and regulated by developmental mechanisms. The molecular bases of cognitive development are not well understood. We provide evidence for the involvement of the α2 isoform of Rac-specific guanosine triphosphatase (GTPase)-activating protein (RacGAP) α-chimaerin (chimerin) in this process. We generated and analyzed mice with global and conditional knockouts of α-chimaerin and its isoforms (α1-chimaerin and α2-chimaerin) and found that α-chimaerin plays a wide variety of roles in brain function and that the roles of α1-chimaerin and α2-chimaerin are distinct. Deletion of α2-chimaerin, but not α1-chimaerin, beginning during early development results in an increase in contextual fear learning in adult mice, whereas learning is not altered when α2-chimaerin is deleted only in adulthood. Our findings suggest that α2-chimaerin acts during development to establish normal cognitive ability in adulthood.
神经科学中的一个主要关注点是成年期的认知能力如何受到发育机制的影响和调控。认知发展的分子基础尚未得到充分理解。我们提供了证据表明，Rac特异性鸟苷三磷酸酶（GTP酶）激活蛋白（RacGAP）α-嵌合蛋白（chimerin）的α2亚型参与了这一过程。我们构建并分析了α-嵌合蛋白及其亚型（α1-嵌合蛋白和α2-嵌合蛋白）的全身性和条件性基因敲除小鼠，发现α-嵌合蛋白在脑功能中发挥着多种作用，且α1-嵌合蛋白和α2-嵌合蛋白的作用各不相同。在早期发育过程中开始缺失α2-嵌合蛋白而非α1-嵌合蛋白，会导致成年小鼠的情境恐惧学习增加，而仅在成年期缺失α2-嵌合蛋白时，学习能力并未改变。我们的研究结果表明，α2-嵌合蛋白在发育过程中发挥作用，以建立成年期的正常认知能力。
