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PMID: 20010819 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature neuroscience ·Vol. 13 ·No. 1 ·2010-01-00 ·Pages 36-44

Arendt KL, Royo M, Fernández-Monreal M, Knafo S, Petrok CN, Martens JR, Esteban JA

Abstract

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.

MeSH Terms
Animals Animals, Newborn Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics,metabolism Carrier Proteins/genetics Dendrites/metabolism,ultrastructure Dendritic Spines/metabolism,ultrastructure Disks Large Homolog 4 Protein Enzyme Inhibitors/pharmacology Excitatory Postsynaptic Potentials/drug effects,physiology Green Fluorescent Proteins/genetics Hippocampus/cytology Immunoprecipitation Intracellular Signaling Peptides and Proteins/metabolism Long-Term Potentiation/drug effects,physiology Membrane Proteins/metabolism Microscopy, Immunoelectron/methods Mutagenesis, Site-Directed/methods Nerve Tissue Proteins/genetics Organ Culture Techniques Patch-Clamp Techniques/methods Phosphatidylinositol 3-Kinases/physiology Phosphatidylinositol Phosphates/metabolism Phosphatidylinositols/metabolism Phosphoinositide-3 Kinase Inhibitors Presynaptic Terminals/physiology,ultrastructure Protein Binding Protein Transport/drug effects,physiology Pyramidal Cells/cytology,ultrastructure Rats Receptors, AMPA/genetics,metabolism Synapses/drug effects,physiology,ultrastructure Synaptic Transmission/drug effects,physiology Time Factors Transfection/methods
Chemicals
Carrier Proteins Disks Large Homolog 4 Protein Dlg4 protein, rat Enzyme Inhibitors Grip1 protein, rat Intracellular Signaling Peptides and Proteins Membrane Proteins Nerve Tissue Proteins Phosphatidylinositol Phosphates Phosphatidylinositols Phosphoinositide-3 Kinase Inhibitors Receptors, AMPA enhanced green fluorescent protein phosphatidylinositol 3,4,5-triphosphate Green Fluorescent Proteins Calcium-Calmodulin-Dependent Protein Kinase Type 2
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Arendt Kristin L
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Royo María
Fernández-Monreal Mónica
Knafo Shira
Petrok Cortney N
Martens Jeffrey R
Esteban José A
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.2462
Published
2010-01-00
Epub
2009-00-13
Pages
36-44
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC2810846
Subset
IM
Grants
NIMH NIH HHS · R01 MH070417 · United States
NIMH NIH HHS · R01 MH070417-03 · United States
External Links
PubMed source DOI: 10.1038/nn.2462 PMC Full Text View journal details
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