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 was specific for synaptic, but not extrasynaptic, AMPA receptors, nor for NMDA receptors. PIP 3 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 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.
Bibliographical noteFunding Information:
We thank R. Holz (University of Michigan) for the plasmid containing the PH-PLC sequence, A. Lee (University of Michigan) for the plasmid containing the catalytic domain of mouse PI3K (p110α), C. Dotti (Katholieke Universiteit Leuven) for the membrane-anchored GFP-CAAX construct, R. Malinow (University of California, San Diego) for the SEP-GluA2 construct and L. Chen (University of California, Berkeley) for facilitating some of the experiments carried out by K.L.A. We also thank S. Jurado and members of the Esteban laboratory for critical reading of this manuscript, and S. Fisher, E. Stuenkel, G. Murphy and R. Holz for discussions. 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.
ASJC Scopus subject areas
- Neuroscience (all)