Differential Roles of Postsynaptic Density-93 Isoforms in Regulating Synaptic Transmission

• Main Authors: Kruger, Juliane M. (Author), Favaro, Plinio D. (Author), Liu, Mingna (Contributor), Kitlinska, Agata (Author), Huang, Xiaojie (Author), Raabe, Monika (Author), Akad, Derya S. (Author), Liu, Yanling (Author), Urlaub, Henning (Author), Dong, Yan (Author), Xu, Weifeng (Contributor), Schluter, Oliver M. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences (Contributor), Picower Institute for Learning and Memory (Contributor)
• Format: Article
• Language: English
• Published: Society for Neuroscience, 2014-09-02T18:10:09Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institute of Mental Health (U.S.) (MH080310)