Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3 integrins.
At synapses, cell adhesion molecules (CAMs) provide the molecular framework for coordinating signaling events across the synaptic cleft. Among synaptic CAMs, the integrins, receptors for extracellular matrix proteins and counterreceptors on adjacent cells, are implicated in synapse maturation and plasticity and memory formation. However, little is known about the molecular mechanisms of integrin action at central synapses. Here, we report that postsynaptic beta3 integrins control synaptic strength by regulating AMPA receptors (AMPARs) in a subunit-specific manner. Pharmacological perturbation targeting beta3 integrins promotes endocytosis of GluR2-containing AMPARs via Rap1 signaling, and expression of beta3 integrins produces robust changes in the abundance and composition of synaptic AMPARs without affecting dendritic spine structure. Importantly, homeostatic synaptic scaling induced by activity deprivation elevates surface expression of beta3 integrins, and in turn, beta3 integrins are required for synaptic scaling. Our findings demonstrate a key role for integrins in the feedback regulation of excitatory synaptic strength.
Cingolani
Lorenzo A
LA
MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, Gower Street, London WC1E 6BT, UK. l.cingolani@ucl.ac.uk
Thalhammer
Agnes
A
Yu
Lily M Y
LM
Catalano
Myriam
M
Ramos
Timothy
T
Colicos
Michael A
MA
Goda
Yukiko
Y
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D018846:Excitatory Amino Acids / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D053778:Thiazolidines / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D020827:rap1 GTP-Binding Proteins
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D018846:Excitatory Amino Acids; D039661:Integrin beta3; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D018091:Receptors, AMPA; D053778:Thiazolidines; C057986:echistatin; D004533:Egtazic Acid; D020827:rap1 GTP-Binding Proteins; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C037067:latrunculin A