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Differential roles of postsynaptic density-93 isoforms in regulating synaptic transmission.

In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission.

Pubmed ID: 24068818 RIS Download

Mesh terms: Animals | Cells, Cultured | Gene Expression Regulation, Developmental | Guanylate Kinases | Hippocampus | Intracellular Signaling Peptides and Proteins | Membrane Proteins | Mice | Neurons | Protein Isoforms | Rats | Rats, Wistar | Receptors, AMPA | Synaptic Transmission | Transcription, Genetic

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Associated grants

  • Agency: NIMH NIH HHS, Id: K99 MH080310
  • Agency: NIMH NIH HHS, Id: R00 MH080310
  • Agency: NIDA NIH HHS, Id: R01 DA023206
  • Agency: NIMH NIH HHS, Id: MH080310

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