PIP3 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 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.
Arendt
Kristin L
KL
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Royo
María
M
Fernández-Monreal
Mónica
M
Knafo
Shira
S
Petrok
Cortney N
CN
Martens
Jeffrey R
JR
Esteban
José A
JA
D000818:Animals; D000831:Animals, Newborn; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D016253:Microscopy, Immunoelectron / Q000379:methods; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017729:Presynaptic Terminals / Q000502:physiology / Q000648:ultrastructure; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology* / Q000648:ultrastructure; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018091:Receptors, AMPA; C501449:Dlg4 protein, rat; C491308:Grip1 protein, rat; C485184:enhanced green fluorescent protein; C060974:phosphatidylinositol 3,4,5-triphosphate