| Annotated protein: | Disks large homolog 4 (Postsynaptic density protein 95) (PSD-95) (Synapse-associated protein 90) (SAP-90) (SAP90). Gene symbol: DLG4. Taxonomy: Mus musculus (Mouse). Uniprot ID: Q62108 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ DLG4 |
| Ontology domain: | Biological Process |
| SynGO term: | neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645) |
| Synapse type(s): | hippocampus, glutamatergic |
| Annotated paper: | Elias GM, et al. "Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins" Neuron. 2006 Oct 19;52(2):307-20 PMID:17046693 |
| Figure(s): | Figures 2-8 |
| Annotation description: | PSD-95 and PSD-93 are the dominant PSD-MAGUKs responsible for the synaptic targeting of AMPA receptors at mature synapses. Previous work showed robust PSD-95 and PSD-93 protein expression occurs later during postnatal development (~P35, Sans et al., 2000). Fig. 3: "PSD-95 Is Necessary for AMPA-R Clustering in a Subset of Synapses" "PSD-93 overexpression strongly enhances AMPA-R EPSCs (Fig. 3B1-3B2)." NMDA-R EPSCs were unaffected by PSD-93 knockdown (Fig. 3B1-3B3). shRNA knockdown of PSD-93 resulted a 48% selective reduction in the size AMPA-R EPSCs (Figures 3C1 and 3C2)."The effect on AMPA-R transmission is target-specific" Expression of PSD-93 shRNA in PSD-93 KO slices had no effect on AMPAR or NMDAR EPSCs (Fig. 3D1-3D3). "PSD-93 determine the synaptic content of AMPARs" Knockdown of PSD-93 reduced of the frequency of mEPSCs (Figure 3G) but had no effect on the amplitude (Fig. 3E-3F), suggesting "that AMPA-Rs are lost from a subset of synapses." Fig. 4: "Impaired AMPA-R mediated synaptic transmission in PSD-93/PSD-93 double KO mice" Double KO mice had a 55% reduction in synaptic transmission (field input/output curves, Fig. 4B) and ~50% reduction in AMPA/ NMDA EPSC ratio (Fig. 4C) compared to WT. There was a significant reduction in the frequency of mEPSCs but no change in the amplitude (Fig. 4D-4E). Consistent with these data, western blot analysis of hippocampal homogenates from PSD-95/PSD-93 double KO mice and litter mate controls showed no difference in the total amounts of GluR1, GluR2, and NR-1 (Fig. 4H-4I) but a significant loss of GluR1 and GluR2, but not NR1, from the PSD-enriched fraction (Fig. 4J-4K). Fig. 5: "Functional Compensation by SAP-102 in PSD-95/PSD-93 Double KO Mice" While SAP97 protein expression was unchanged, there was a 20% increase in SAP102 protein in both the total and PSD-enriched fractions (Fig. 5A-5B) suggesting, "SAP-102 may cluster the AMPA-Rs that mediate the remaining synaptic transmission." Fig. 5 and 8: "The role of PSD MAGUK proteins in synaptic AMPA-R targeting is developmentally regulated; SAP-102 is primarily responsible for clustering in neonatal synapses, whereas PSD-95 and PSD-93 primarily anchor proteins in mature synapses" Fig.6-7: "PSD-95 and PSD-93 are jointly required for normal synaptic expression of NMDA-Rs" Knockdown of either PSD-95 or PSD-93 selectively reduced AMPAR transmission. Simultaneous knockdown of both PSD-95 and PSD-93 reduced AMPA-R and NMDA-R EPSCs, suggesting, "PSD-95 and PSD-93 are key structural scaffolding elements of the PSD jointly required for proper synaptic expression of NMDA receptors." Figure 1. shRNAs Against PSD-95, PSD-93, and SAP-102 Cause Selective Knockdown in COS-7 Cells and Hippocampal Neurons. Figure 9. "Slice Culture Scheme" shows how mature vs immature synaptic transmission was assayed in hippocampal slices. |
| Evidence tracking, Biological System: | Intact tissue Cultured neurons |
| Evidence tracking, Protein Targeting: | Genetic transformation (eg; knockout, knockin, mutations) RNAi / shRNA Over-expression Antibody (detection) |
| Evidence tracking, Experiment Assay: | Confocal Whole-cell patch clamp Field recordings Electrophysiology (generic) Western blot Biochemical fractionation (generic) |
| Annotator(s): | Hana Goldschmidt (ORCID:0000-0002-5676-366X) Richard Huganir (ORCID:0000-0001-9783-5183) |
| Lab: | Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205, USA |
| Additional literature: | Figure 3: "Patterns of developmental expression of MAGUKs. P2, P10, P35, and 6 month (6M) rat hippocampus homogenates." Western blot analysis. Figure 4-5: Immunogold labeling of SAP102 and PSD-95 in the CA1 stratum radiatum of the hippocampus during development. Table 2. "Summary of immunogold labeling for PSD-95 and SAP-102" @ PMID:10648730 |
| SynGO annotation ID: | 2636 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |