PIP 3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane
Nat Neurosci. 2009-12-13; 13(1): 36-44
DOI: 10.1038/nn.2462
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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.