The role of SAP97 in synaptic glutamate receptor dynamics.
Proteins of the PSD-95-like membrane-associated guanylate kinase (PSD-MAGUK) family are vital for trafficking AMPA receptors (AMPARs) to synapses, a process necessary for both basal synaptic transmission and forms of synaptic plasticity. Synapse-associated protein 97 (SAP97) exhibits protein interactions, such as direct interaction with the GluA1 AMPAR subunit, and subcellular localization (synaptic, perisynaptic, and dendritic) unique within this protein family. Due in part to the lethality of the germline knockout of SAP97, this protein's role in synaptic transmission and plasticity is poorly understood. We found that overexpression of SAP97 during early development traffics AMPARs and NMDA receptors (NMDARs) to synapses, and that SAP97 rescues the deficits in AMPAR currents normally seen in PSD-93/-95 double-knockout neurons. Mature neurons that have experienced the overexpression of SAP97 throughout development exhibit enhanced AMPAR and NMDAR currents, as well as faster NMDAR current decay kinetics. In loss-of-function experiments using conditional SAP97 gene deletion, we recorded no deficits in glutamatergic transmission or long-term potentiation. These results support the hypothesis that SAP97 is part of the machinery that traffics glutamate receptors and compensates for other PSD-MAGUKs in knockout mouse models. However, due to functional redundancy, other PSD-MAGUKs can presumably compensate when SAP97 is conditionally deleted during development.
Howard
Mackenzie A
MA
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
Elias
Guillermo M
GM
Elias
Laura A B
LA
Swat
Wojciech
W
Nicoll
Roger A
RA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission
D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C000614189:Dlg1 protein, mouse