Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins.
Trafficking of AMPA receptors (AMPA-Rs) to and from synapses controls the strength of excitatory synaptic transmission. However, proteins that cluster AMPA-Rs at synapses remain poorly understood. Here we show that PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs) mediate this synaptic targeting, and we uncover a remarkable functional redundancy within this protein family. By manipulating endogenous neuronal PSD-MAGUK levels, we find that both PSD-95 and PSD-93 independently mediate AMPA-R targeting at mature synapses. We also reveal unanticipated synapse heterogeneity as loss of either PSD-95 or PSD-93 silences largely nonoverlapping populations of excitatory synapses. In adult PSD-95 and PSD-93 double knockout animals, SAP-102 is upregulated and compensates for the loss of synaptic AMPA-Rs. At immature synapses, PSD-95 and PSD-93 play little role in synaptic AMPA-R clustering; instead, SAP-102 dominates. These studies establish a PSD-MAGUK-specific regulation of AMPA-R synaptic expression that establishes and maintains glutamatergic synaptic transmission in the mammalian central nervous system.
Elias
Guillermo M
GM
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143, USA.
Funke
Lars
L
Stein
Valentin
V
Grant
Seth G
SG
Bredt
David S
DS
Nicoll
Roger A
RA
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D015536:Down-Regulation / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011940:Receptor Aggregation / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C501451:Mpp2 protein, rat; D009479:Neuropeptides; D018091:Receptors, AMPA; D018698:Glutamic Acid; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases