Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Cell Differentiation / physiology*
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Cells, Cultured
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Chlorocebus aethiops
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Dendritic Spines / metabolism*
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Dendritic Spines / ultrastructure
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Disks Large Homolog 4 Protein
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Down-Regulation / physiology
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Glutamic Acid / metabolism
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Guanylate Kinases
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Hippocampus / embryology
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Hippocampus / metabolism
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Hippocampus / ultrastructure
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Organ Culture Techniques
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Protein Transport / physiology
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Rats
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Receptor Aggregation / physiology
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Receptors, AMPA / metabolism*
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Synapses / metabolism*
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Synapses / ultrastructure
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Synaptic Membranes / metabolism
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Synaptic Membranes / ultrastructure
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Synaptic Transmission / physiology*
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Mpp2 protein, rat
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Neuropeptides
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Receptors, AMPA
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Glutamic Acid
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Dlgh3 protein, mouse
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Guanylate Kinases