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O-GlcNAc transferase controls excitatory synapse development and AMPA receptor expression in an activity-dependent manner
Umeå University, Faculty of Medicine, Department of Clinical Sciences. Umeå University, Faculty of Medicine, Department of Medical and Translational Biology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).ORCID iD: 0009-0000-9528-8745
Umeå University, Faculty of Medicine, Department of Clinical Sciences. Umeå University, Faculty of Medicine, Department of Medical and Translational Biology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
2026 (English)In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 20, article id 1799487Article in journal (Refereed) Published
Abstract [en]

Brain development and neural circuit function depend on the formation and termination of excitatory synapses. The regulation of excitatory synapse plasticity has long been associated with neuronal activity. In addition to neuronal activity, emerging data show that body metabolism affects synaptic plasticity. However, it is unclear how neuronal activity and metabolic signaling may interact to control the number and function of excitatory synapses. The nutrient sensor O-GlcNAc transferase (OGT), an enzyme that catalyzes O-GlcNAcylation of cytoplasmic and nuclear proteins depending on the metabolic state of the body, has been implicated in excitatory synapse maturation, but its activity-dependent roles and underlying mechanisms are unclear. Here, we investigated how OGT regulates excitatory synapse structure, number and AMPA-type glutamate receptors (AMPARs) in cultured hippocampal neurons under normal and activity-suppressed conditions. We show that OGT overexpression selectively enhances accumulation of the AMPARs subunit GluA1 in dendritic spines at a mature developmental stage (DIV14), but not during early development (DIV7). Chronic suppression of neuronal activity with tetrodotoxin (TTX) abolished the OGT-dependent increase in GluA1 expression, indicating that OGT-mediated regulation of AMPARs is activity-dependent. In parallel, OGT overexpression promoted coordinated growth and maturation of excitatory synapses, increasing the size and intensity of postsynaptic PSD-95 and presynaptic vGluT1 puncta, particularly at colocalized synaptic sites. These structural effects, as well as OGT-induced increases in excitatory synapse number, were eliminated by activity blockade. Together, our findings identify the nutrient sensor OGT as an activity-dependent regulator of excitatory synapse maturation and AMPARs accumulation, revealing a molecular mechanism by which neuronal activity and metabolic signaling can be integrated to shape synaptic connectivity and function.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2026. Vol. 20, article id 1799487
Keywords [en]
AMPARs, dendritic spine, excitatory synapse, O-GlcNAc transferase, tetrodotoxin
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-252682DOI: 10.3389/fncel.2026.1799487ISI: 001729601600001PubMedID: 41924559Scopus ID: 2-s2.0-105034551475OAI: oai:DiVA.org:umu-252682DiVA, id: diva2:2061029
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2022-01024Umeå UniversityThe Swedish Brain FoundationRegion VästerbottenThe Kempe FoundationsFredrik och Ingrid Thurings StiftelseStiftelsen Sigurd och Elsa Goljes minneMärta Lundqvists FoundationAvailable from: 2026-05-20 Created: 2026-05-20 Last updated: 2026-05-20Bibliographically approved

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Han, LinkunLagerlöf, Olof

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