Synapse-specific regulation of AMPA receptor function by PSD-95.
PSD-95 is a major protein found in virtually all mature excitatory glutamatergic synapses in the brain. Here, we have addressed the role of PSD-95 in controlling glutamatergic synapse function by generating and characterizing a PSD-95 KO mouse. We found that the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)subtype of glutamate receptor (AMPAR)-mediated synaptic transmission was reduced in these mice. Two-photon (2P) uncaging of MNI-glutamate onto individual spines suggested that the decrease in AMPAR function in the PSD-95 KO mouse stems from an increase in the proportion of "silent" synapses i.e., synapses containing N-methyl-d-aspartate (NMDA) receptors (NMDARs) but no AMPARs. Unexpectedly, the silent synapses in the KO mouse were located onto morphologically mature spines. We also observed that a significant population of synapses appeared unaffected by PSD-95 gene deletion, suggesting that the functional role of PSD-95 displays synapse-specificity. In addition, we report that the decay of NMDAR-mediated current was slower in KO mice: The contribution of NR2B subunit containing receptors to the NMDAR-mediated synaptic current was greater in KO mice. The greater occurrence of silent synapses might be related to the greater magnitude of potentiation after long-term potentiation induction observed in these mice. Together, these results suggest a synapse-specific role for PSD-95 in controlling synaptic function that is independent of spine morphology.
Béïque
Jean-Claude
JC
Department of Neuroscience, Johns Hopkins University School of Medicine and Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
Lin
Da-Ting
DT
Kang
Myoung-Goo
MG
Aizawa
Hiro
H
Takamiya
Kogo
K
Huganir
Richard L
RL
D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D017353:Gene Deletion; D005971:Glutamates / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000502:physiology*; D007211:Indoles / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
C440256:4-methoxy-7-nitroindolinyl-glutamate; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D005971:Glutamates; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D051528:Guanylate Kinases