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.
European Neuroscience Institute, 37077 Göttingen, Germany, Göttingen Graduate School for Neurosciences and Molecular Biosciences, 37077 Göttingen, Germany, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02319, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany, International Max Planck Research School for Neuroscience, 37077 Göttingen, Germany, Bioanalytics, Department of Clinical Chemistry, 37075 Göttingen, Germany, and Department of Neuroscience, University of Pittsburgh, Pennsylvania 15260.
Juliane M
JM
Krüger
Plinio D
PD
Favaro
Mingna
M
Liu
Agata
A
Kitlinska
Xiaojie
X
Huang
Monika
M
Raabe
Derya S
DS
Akad
Yanling
Y
Liu
Henning
H
Urlaub
Yan
Y
Dong
Weifeng
W
Xu
Oliver M
OM
Schlüter
D000818:Animals; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D014158:Transcription, Genetic
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C501451:Mpp2 protein, rat; D020033:Protein Isoforms; D018091:Receptors, AMPA; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases