Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development
Open accessAbstract
The development of glutamatergic synapses involves changes in the number and type of receptors present at the postsynaptic density. To elucidate molecular mechanisms underlying these changes, we combine in utero electroporation of constructs that alter the molecular composition of developing synapses with dual whole-cell electrophysiology to examine synaptic transmission during two distinct developmental stages. We find that SAP102 mediates synaptic trafficking of AMPA and NMDA receptors during synaptogenesis. Surprisingly, after synaptogenesis, PSD-95 assumes the functions of SAP102 and is necessary for two aspects of synapse maturation: the developmental increase in AMPA receptor transmission and replacement of NR2B-NMDARs with NR2A-NMDARs. In PSD-95/PSD-93 double-KO mice, the maturational replacement of NR2B- with NR2A-NMDARs fails to occur, and PSD-95 expression fully rescues this deficit. This study demonstrates that SAP102 and PSD-95 regulate the synaptic trafficking of distinct glutamate receptor subtypes at different developmental stages, thereby playing necessary roles in excitatory synapse development.
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PSD-95 is a major structural component of the PSD core layer, oriented vertically to the postsynaptic membrane, and binds and organizes both AMPA and NMDA glutamate receptors.
“PSD-95, a prominent member of the MAGUK family, is a major structural component of the PSD core layer [39]. It is oriented vertically to the postsynaptic membrane, strategically positioned to bind and organize both AMPA and NMDA glutamate receptors [40,41].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [40]
MAGUK proteins, including PSD-95 and SAP102, are primary scaffolds that interact with GluN2 subunits, anchoring and stabilizing NMDARs at glutamatergic synapses.
“MAGUK proteins, including PSD-95 and synapse-associated protein 102 (SAP102), are primary scaffolds that interact with GluN2 subunits, anchoring and stabilizing NMDARs at glutamatergic synapses [40].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [40]
PSD-95 assumes the synaptic trafficking function during synapse maturation, including the replacement of NR2B-NMDARs with NR2A-NMDARs.
“Notably, SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis [49], while PSD-95 assumes this function during synapse maturation, including the crucial replacement of NR2B-NMDARs with NR2A-NMDARs [40,50].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [40]
A significant developmental switch occurs in higher brain regions, transitioning from predominantly GluN2B-containing NMDARs in immature synapses to GluN2A-containing NMDARs in mature synapses.
“A significant developmental switch occurs in higher brain regions, transitioning from predominantly GluN2B-containing NMDARs in immature synapses to GluN2A-containing NMDARs in mature synapses [40].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [40]
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Molecular Physiology of the Neuronal Synapse
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“Notably, SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis [49], while PSD-95 assumes this function during synapse maturation, including the crucial replacement of NR2B-NMDARs with NR2A-NMDARs [40,50].”
Influential
- Authors
- Elias, G. M., Elias, L. A. B., Apostolides, P. F., Kriegstein, A. R., & Nicoll, R. A.
- Affiliations
- Neuroscience Graduate Program,
- Department of Cellular and Molecular Pharmacology,
- Institute for Regeneration Medicine, and
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-12-30
- Volume
- 105
- Issue
- 52
- Pages
- 20953-20958
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2634944
- OpenAlex
- W2103222728
- Cited by
- 223
- References
- 2
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 15 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 8 · 2019: 16 · 2018: 12 · 2017: 11 · 2016: 21 · 2015: 11 · 2014: 15 · 2013: 11 · 2012: 15
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R37MH038256)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- AMPA receptors, NMDA receptor, SAP102, PSD-95, PSD-93, synaptogenesis, synapse maturation, glutamatergic synapses, postsynaptic density, receptor trafficking, synaptic transmission
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Female, Humans, Membrane Proteins, Synaptic Transmission, Neuropeptides, Pregnancy, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Mice, Rats, Guanylate Kinases
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