Differential requirement for NMDAR activity in SAP97β-mediated regulation of the number and strength of glutamatergic AMPAR-containing synapses.
PSD-95-like, disc-large (DLG) family membrane-associated guanylate kinase proteins (PSD/DLG-MAGUKs) are essential for regulating synaptic AMPA receptor (AMPAR) function and activity-dependent trafficking of AMPARs. Using a molecular replacement strategy to replace endogenous PSD-95 with SAP97β, we show that the prototypic β-isoform of the PSD-MAGUKs, SAP97β, has distinct NMDA receptor (NMDAR)-dependent roles in regulating basic properties of AMPAR-containing synapses. SAP97β enhances the number of AMPAR-containing synapses in an NMDAR-dependent manner, whereas its effect on the size of unitary synaptic response is not fully dependent on NMDAR activity. These effects contrast with those of PSD-95α, which increases both the number of AMPAR-containing synapses and the size of unitary synaptic responses, with or without NMDAR activity. Our results suggest that SAP97β regulates synaptic AMPAR content by increasing surface expression of GluA1-containing AMPARs, whereas PSD-95α enhances synaptic AMPAR content presumably by increasing the synaptic scaffold capacity for synaptic AMPARs. Our approach delineates discrete effects of different PSD-MAGUKs on principal properties of glutamatergic synaptic transmission. Our results suggest that the molecular diversity of PSD-MAGUKs can provide rich molecular substrates for differential regulation of glutamatergic synapses in the brain.
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts;
Mingna
M
Liu
Laura D
LD
Lewis
Rebecca
R
Shi
Emery N
EN
Brown
Weifeng
W
Xu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D013570:Synaptic Membranes / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000076122:Disks Large Homolog 4 Protein; C501119:Dlg1 protein, rat; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate
DLG-MAGUK; PSD-MAGUK; excitatory synapse; hippocampus; mEPSC