Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins

Neuron. 2006 Oct 19;52(2):307-20. doi: 10.1016/j.neuron.2006.09.012.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Dendritic Spines / metabolism*
  • Dendritic Spines / ultrastructure
  • Disks Large Homolog 4 Protein
  • Down-Regulation / physiology
  • Glutamic Acid / metabolism
  • Guanylate Kinases
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • Hippocampus / ultrastructure
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Organ Culture Techniques
  • Protein Transport / physiology
  • Rats
  • Receptor Aggregation / physiology
  • Receptors, AMPA / metabolism*
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Synaptic Membranes / metabolism
  • Synaptic Membranes / ultrastructure
  • Synaptic Transmission / physiology*


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mpp2 protein, rat
  • Neuropeptides
  • Receptors, AMPA
  • Glutamic Acid
  • Dlgh3 protein, mouse
  • Guanylate Kinases