{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:55:32Z","timestamp":1791212132567,"version":"4.1.0"},"posted":{"date-parts":[[2026,1,26]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIMH","award":["R01 MH130428"],"award-info":[{"award-number":["R01 MH130428"]}]},{"name":"NIMH","award":["R01 MH099114"],"award-info":[{"award-number":["R01 MH099114"]}]},{"name":"NINDs","award":["R01 NS115471"],"award-info":[{"award-number":["R01 NS115471"]}]},{"name":"NEI","award":["R01 EY030169"],"award-info":[{"award-number":["R01 EY030169"]}]},{"name":"NEI","award":["R01 EY032506"],"award-info":[{"award-number":["R01 EY032506"]}]},{"name":"NIA","award":["R01 AG078796"],"award-info":[{"award-number":["R01 AG078796"]}]},{"name":"NIH","award":["S10 OD032464"],"award-info":[{"award-number":["S10 OD032464"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are critical for activity-dependent synapse maturation and circuit development.\n                  <jats:italic>De novo<\/jats:italic>\n                  missense mutations in AMPAR subunits are linked to neurodevelopmental disorders (NDDs), yet how these variants disrupt neuronal function remains unclear. Here, we examine a recurrent pathogenic mutation in the GluA1 subunit (GRIA1 p.A636T) that alters AMPAR function and is associated with autism spectrum disorder (ASD) and intellectual disability (ID). Using GluA1\n                  <jats:sup>A636T<\/jats:sup>\n                  knock-in mice of either sex, we identify impairments in hippocampal-dependent learning and working memory. Quantitative proteomics combined with bulk RNA-seq revealed age-dependent molecular remodeling in mutant hippocampus. Synaptic protein alterations were present in juvenile and adult mice, whereas a pronounced upregulation of mitochondrial and glial-associated proteins emerged more strongly in adulthood. Transcriptomic analyses showed partial concordance and highlighted divergence between RNA and protein regulation. Consistent with these molecular changes, there were increases in markers of oxidative stress in juvenile and adult mutant animals, whereas altered mitochondria morphology emerged selectively in adult mutants. Electrophysiological recordings demonstrated reduced basal excitatory transmission, persistence of silent synapses in adulthood and exaggerated activity-dependent synaptic potentiation, which were associated with reduced spine size consistent with impaired synapse maturation. Together, these findings indicate that a pathogenic AMPAR mutation disrupts developmental synapse maturation with secondary metabolic adaptations emerging over time.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Mutations in genes encoding AMPA-type glutamate receptors are increasingly linked to neurodevelopmental disorders, including autism and intellectual disability. However, how these mutations disrupt brain function and development remains poorly understood. Using a mouse model carrying a recurrent disease-associated mutation in the GluA1 AMPA receptor subunit, we show that the presence of this mutant subunit protein impairs the normal maturation of excitatory synapses in the hippocampus. Mutant mice retain immature \u201csilent\u201d synapses into adulthood, exhibit abnormal synaptic plasticity, reduced spine size, and deficits in learning and memory. Molecular analyses reveal age-dependent remodeling of synaptic and mitochondrial proteins, suggesting that metabolic changes arise secondary to disrupted synapse development. These findings clarify how pathogenic AMPA receptor variants alter brain function over time.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.26.701845","type":"posted-content","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T08:10:22Z","timestamp":1769501422000},"source":"Crossref","is-referenced-by-count":1,"title":["A pathogenic AMPAR mutation disrupts hippocampal synapse maturation and homeostasis"],"prefix":"10.64898","author":[{"given":"Jian","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60613"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Zhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 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