Reduced Phosphatidylinositol 4,5-Bisphosphate Synthesis Impairs Inner Ear Ca2+ Signaling And High-Frequency Hearing Acquisition

Phosphatidylinositol phosphate kinase type 1 gamma (PIPKI gamma) is a key enzyme in the generation of phosphatidylinositol 4,5-bisphosphate [PI (4,5)P-2] and is expressed at high levels in the nervous system. Homozygous knockout mice lacking this enzyme die postnatally within 24 h, whereas PIPKI gamma(+/-) siblings breed normally and have no reported phenotype. Here we show that adult PIPKI gamma(+/-) mice have dramatically elevated hearing thresholds for high-frequency sounds. During the first postnatal week we observed a reduction of ATP-dependent Ca2+ signaling activity in cochlear nonsensory cells. Because Ca2+ signaling under these conditions depends on inositol-1,4,5-trisphosphate generation from phospholipase C (PLC)-dependent hydrolysis of PI(4,5)P-2, we conclude that (i) PIPKI gamma is primarily responsible for the synthesis of the receptor-regulated PLC-sensitive PI(4,5)P-2 pool in the cell syncytia that supports auditory hair cells; (ii) spatially graded impairment of this signaling pathway in cochlear nonsensory cells causes a selective alteration in the acquisition of hearing in PIPKI gamma(+/-) mice. This mouse model also suggests that PIPKI gamma may determine the level of gap junction contribution to cochlear development.