Nakazawa Takanobu, Komai Shoji, Watabe Ayako M, Kiyama Yuji, Fukaya Masahiro, Arima-Yoshida Fumiko, Horai Reiko, Sudo Katsuko, Ebine Kazumi, Delawary Mina, Goto June, Umemori Hisashi, Tezuka Tohru, Iwakura Yoichiro, Watanabe Masahiko, Yamamoto Tadashi, Manabe Toshiya
Division of Oncology, Department of Cancer Biology, University of Tokyo, Tokyo, Japan.
EMBO J. 2006 Jun 21;25(12):2867-77. doi: 10.1038/sj.emboj.7601156. Epub 2006 May 18.
Phosphorylation of neural proteins in response to a diverse array of external stimuli is one of the main mechanisms underlying dynamic changes in neural circuitry. The NR2B subunit of the NMDA receptor is tyrosine-phosphorylated in the brain, with Tyr-1472 its major phosphorylation site. Here, we generate mice with a knockin mutation of the Tyr-1472 site to phenylalanine (Y1472F) and show that Tyr-1472 phosphorylation is essential for fear learning and amygdaloid synaptic plasticity. The knockin mice show impaired fear-related learning and reduced amygdaloid long-term potentiation. NMDA receptor-mediated CaMKII signaling is impaired in YF/YF mice. Electron microscopic analyses reveal that the Y1472F mutant of the NR2B subunit shows improper localization at synapses in the amygdala. We thus identify Tyr-1472 phosphorylation as a key mediator of fear learning and amygdaloid synaptic plasticity.
响应各种外部刺激时神经蛋白的磷酸化是神经回路动态变化的主要机制之一。NMDA受体的NR2B亚基在大脑中发生酪氨酸磷酸化，其主要磷酸化位点为Tyr-1472。在此，我们构建了将Tyr-1472位点敲入突变为苯丙氨酸（Y1472F）的小鼠，并表明Tyr-1472磷酸化对于恐惧学习和杏仁核突触可塑性至关重要。敲入小鼠表现出与恐惧相关的学习受损以及杏仁核长时程增强减弱。YF/YF小鼠中NMDA受体介导的CaMKII信号传导受损。电子显微镜分析显示，NR2B亚基的Y1472F突变体在杏仁核突触处定位不当。因此，我们确定Tyr-1472磷酸化是恐惧学习和杏仁核突触可塑性的关键介质。
