PIP(3) controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane

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 (PIP(3)) at the postsynaptic terminal is necessary for sustaining synaptic function in rat hippocampal neurons. This requirement is specific for synaptic, but not for extrasynaptic, AMPA receptors, nor NMDA receptors. We found that PIP(3) down-regulation impairs PSD-95 accumulation in spines. Concomitantly, AMPA receptors become more mobile and migrate from the postsynaptic density towards the perisynaptic membrane within the spine, leading to synaptic depression. Interestingly, these effects are only revealed after prolonged inhibition of PIP(3) synthesis or by direct quenching of this phosphoinositide at the postsynaptic cell. Therefore, we conclude that a slow, but constant turnover of PIP(3) at synapses is required for maintaining AMPA receptor clustering and synaptic strength under basal conditions.