Inositol polyphosphate multikinase mediates extinction of fear memory

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 3,4,5-trisphosphate, 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.

Keywords: fear extinction; inositol polyphosphate multikinase; long-term potentiation; memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Enzyme Activation
  • Extinction, Psychological*
  • Fear / psychology*
  • Gene Deletion
  • Memory*
  • Mice
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Prosencephalon / physiology
  • Signal Transduction
  • Up-Regulation


  • Phosphotransferases (Alcohol Group Acceptor)
  • inositol polyphosphate multikinase