PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not wel...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-12, Vol.112 (50), p.E6983-E6992
Main Authors: Chen, Xiaobing, Levy, Jonathan M., Hou, Austin, Winters, Christine, Azzam, Rita, Sousa, Alioscka A., Leapman, Richard D., Nicoll, Roger A., Reese, Thomas S.
Format: Article
Language:English
Subjects:
Amino acids
Animals
Biological Sciences
Cells, Cultured
Disks Large Homolog 4 Protein
Gene Knockdown Techniques
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Intracellular Signaling Peptides and Proteins - physiology
Kinases
Membrane Proteins - genetics
Membrane Proteins - metabolism
Membrane Proteins - physiology
Membranes
Molecular chemistry
Physiology
PNAS Plus
Post-Synaptic Density - metabolism
Rats
Receptors, AMPA - metabolism
Receptors, N-Methyl-D-Aspartate - metabolism
Tomography
Transmission electron microscopy
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Summary:The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not well understood. Here, we explore the structural and functional roles of MAGUKs at hippocampal excitatory synapses by simultaneous knocking down PSD-95, PSD-93, and synapse-associated protein (SAP)102 and combining electrophysiology and transmission electron microscopic (TEM) tomography imaging to analyze the resulting changes. Acute MAGUK knockdown greatly reduces synaptic transmission mediated by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) andN-methyl-D-aspartate receptors (NMDARs). This knockdown leads to a significant rise in the number of silent synapses, diminishes the size of PSDs without changes in pre- or postsynaptic membrane, and depletes the number of membrane-associated PSD-95–like vertical filaments and transmembrane structures, identified as AMPARs and NMDARs by EM tomography. The differential distribution of these receptor-like structures and dependence of their abundance on PSD size matches that of AMPARs and NMDARs in the hippocampal synapses. The loss of these structures following MAGUK knockdown tracks the reduction in postsynaptic AMPAR and NMDAR transmission, confirming the structural identities of these two types of receptors. These results demonstrate that MAGUKs are required for anchoring both types of glutamate receptors at the PSD and are consistent with a structural model where MAGUKs, corresponding to membrane-associated vertical filaments, are the essential structural proteins that anchor and organize both types of glutamate receptors and govern the overall molecular organization of the PSD.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1517045112