Characterization of a neuronal function of inositol polyphosphate multikinase in the regulation of behavior and signaling transduction

Abstract

Inositol polyphosphate multikinase (IPMK), which is the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphate, also acts as a pleotropic signaling factor in regulating growth and metabolism. To elucidate the behavior and neural functions of IPMK, I generated mice in which IPMK is deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficit in novel object recognition or spatial memory. IPMK conditional knockout mice exhibited normal memory formation for fear conditioning but showed enhanced fear extinction. Microarray and signaling analyses demonstrated that these mice exhibited dysregulated expression of neural genes (e.g., that encoding synaptotagmin-2), accompanied with selective activation of p85 S6 kinase 1 (S6K1) in the amygdala following fear extinction. Electrophysiological analysis further revealed that IPMK conditional knockout mice elicited facilitated hippocampal long-term potentiation. Collectively, these findings suggest that a novel signaling action of IPMK is critically involved in constraining the extinction of fear.