Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD

Neuron. 2008 Jan 24;57(2):248-62. doi: 10.1016/j.neuron.2007.11.027.


The postsynaptic density protein PSD-95 influences synaptic AMPA receptor (AMPAR) content and may play a critical role in LTD. Here we demonstrate that the effects of PSD-95 on AMPAR-mediated synaptic responses and LTD can be dissociated. Our findings suggest that N-terminal-domain-mediated dimerization is important for PSD-95's effect on basal synaptic AMPAR function, whereas the C-terminal SH(3)-GK domains are also necessary for localizing PSD-95 to synapses. We identify PSD-95 point mutants (Q15A, E17R) that maintain PSD-95's influence on basal AMPAR synaptic responses yet block LTD. These point mutants increase the proteolysis of PSD-95 within its N-terminal domain, resulting in a C-terminal fragment that functions as a dominant negative likely by scavenging critical signaling proteins required for LTD. Thus, the C-terminal portion of PSD-95 serves a dual function. It is required to localize PSD-95 at synapses and as a scaffold for signaling proteins that are required for LTD.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Dendritic Spines / physiology
  • Disks Large Homolog 4 Protein
  • Dose-Response Relationship, Radiation
  • Electric Stimulation / methods
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Long-Term Synaptic Depression / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Models, Biological
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Patch-Clamp Techniques / methods
  • Point Mutation / physiology
  • Protein Structure, Tertiary / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / physiology
  • Synapses / physiology*
  • Synaptic Transmission / physiology
  • Synaptic Transmission / radiation effects
  • Transfection / methods


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, AMPA
  • Green Fluorescent Proteins