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

Abstract

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 ␣-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.

Synaptic Consolidation Normalizes AMPAR Quantal Size following MAGUK Loss

“…Previous experiments (Elias et al, 2006) have reported that PSD-93 and PSD-95 each account for half of AMPAR-mediated transmission (but see Krüger et al, 2013), while SAP102 plays a compensatory role if both PSD-93 and PSD-95 are lost. Knockdown of PSD-93 or PSD-95 has been reported to have either no (Elias et al, 2006) or minimal effect (Ehrlich et al, 2007) on NMDAR currents.…”

Calcium‐permeable AMPA receptors and silent synapses in cocaine‐conditioned place preference

“…The PSD‐93 gene is the most complex among the DLG‐MAGUKs; it codes for the highest number of N‐terminal isoforms (Parker et al , ; Krüger et al , ). Consequently, the analysis of PSD‐93 KOs has uncovered multiple, and partly conflicting results on PSD‐93‐mediated regulation of AMPARs.…”

“…Consequently, the analysis of PSD‐93 KOs has uncovered multiple, and partly conflicting results on PSD‐93‐mediated regulation of AMPARs. It was consistently observed that PSD‐95 and PSD‐93 isoforms share some redundancy in regulating AMPAR function, when one is replaced by another or over‐expressed (Elias et al , ; Krüger et al , ). However, results on the loss of PSD‐93 function vary.…”

Adrenergic Gate Release for Spike Timing-Dependent Synaptic Potentiation

“…Hippocampal cultures were prepared from P0–1 mice as described (Krüger et al, 2013). For immune staining, neurons were fixed with 4% paraformaldehyde.…”

“…Immunoprecipitates were separated by Bis-Tris gels (Bonnet et al, 2013), transferred onto nitrocellulose and analyzed using standard procedures (Krüger et al, 2013). …”