PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane

Supplementary information is available on the Nature Neuroscience website.Despite their low abundance, phosphoinositides are critical regulators of intracellular signaling and membrane compartmentalization. However, little is known of phosphoinositide function at the postsynaptic membrane. Here we show that continuous synthesis and availability of phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the postsynaptic terminal is necessary for sustaining synaptic function in rat hippocampal neurons. This requirement was specific for synaptic, but not extrasynaptic, AMPA receptors, nor for NMDA receptors. PIP3 downregulation impaired PSD-95 accumulation in spines. Concomitantly, AMPA receptors became more mobile and migrated from the postsynaptic density toward the perisynaptic membrane within the spine, leading to synaptic depression. Notably, these effects were only revealed after prolonged inhibition of PIP3 synthesis or by direct quenching of this phosphoinositide at the postsynaptic cell. Therefore, we conclude that a slow, but constant, turnover of PIP3 at synapses is required for maintaining AMPA receptor clustering and synaptic strength under basal conditions.This work was supported by grants from the US National Institute of Mental Health (J.A.E. and J.R.M.), the Dana Foundation (J.A.E.) and the Spanish Ministry of Science and Innovation (J.A.E.). M.F.-M. and S.K. are supported by postdoctoral contracts, and M.R. by a predoctoral fellowship, from the Spanish Ministry of Science and Innovation.Peer reviewe