Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 34141 Daejeon, Korea.
Center for Neural Science, New York University, New York, NY 10003.
Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2707-2712. doi: 10.1073/pnas.1812771116. Epub 2019 Jan 28.
Inositol polyphosphate multikinase (IPMK), the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5trisphosphate, also acts as a versatile signaling player in regulating tissue growth and metabolism. To elucidate neurobehavioral functions of IPMK, we generated mice in which IPMK was deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficits in either novel object recognition or spatial memory. IPMK conditional knockout mice formed cued fear memory normally but displayed enhanced fear extinction. Signaling analyses revealed dysregulated expression of neural genes accompanied by selective activation of the mechanistic target of rapamycin (mTOR) regulatory enzyme p85 S6 kinase 1 (S6K1) in the amygdala following fear extinction. The IPMK mutants also manifested facilitated hippocampal long-term potentiation. These findings establish a signaling action of IPMK that mediates fear extinction.
肌醇多聚磷酸激酶（IPMK）是生物合成高肌醇多磷酸盐和磷脂酰肌醇 3,4,5-三磷酸的关键酶，也作为一种多功能信号转导因子，在调节组织生长和代谢中发挥作用。为了阐明 IPMK 的神经行为功能，我们生成了条件性敲除 IPMK 的小鼠，使其兴奋性神经元中的 IPMK 缺失。这些小鼠在新物体识别或空间记忆方面没有表现出缺陷。IPMK 条件性敲除小鼠形成线索性恐惧记忆正常，但表现出增强的恐惧消退。信号分析显示，在恐惧消退后，杏仁核中神经基因的表达失调，伴随着雷帕霉素靶蛋白（mTOR）调节酶 p85 S6 激酶 1（S6K1）的选择性激活。IPMK 突变体还表现出促进海马长时程增强。这些发现确立了 IPMK 的信号转导作用，介导了恐惧消退。
