Differential requirement for NMDAR activity in SAP97β-mediated regulation of the number and strength of glutamatergic AMPAR-containing synapses

• Published in: Journal of neurophysiology Vol. 111; no. 3; pp. 648 - 658
• Main Authors: Liu, Mingna, Lewis, Laura D, Shi, Rebecca, Brown, Emery N, Xu, Weifeng
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2014
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Disks Large Homolog 4 Protein; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Potentials; Membrane Proteins - genetics; Membrane Proteins - metabolism; Neurons - metabolism; Neurons - physiology; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - metabolism; Synapses - physiology; Synaptic Membranes - metabolism; mEPSC; excitatory synapse; hippocampus; DLG-MAGUK; PSD-MAGUK
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00262.2013

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.