{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:05:00Z","timestamp":1784099100839,"version":"3.55.0"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and statistically significant plaque accumulation in the CA1 stratum radiatum by 4 months of age. Hippocampal slice electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, oxidative stress, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident within hippocampal synaptic processes. Morphological analyses demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics identified regionally enriched molecular signatures consistent with differential vulnerability. The CA1 subregion exhibited pronounced downregulation of mitochondria-related transcripts, and single-cell deconvolution resolved this transcriptomic suppression specifically to CA1 pyramidal neurons (CA1.ProS); CA3 and dentate gyrus did not show equivalent mitochondrial pathway suppression. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability. Mitochondrial transcriptomic suppression was anatomically restricted to CA1 pyramidal neurons, establishing a cell-type-specific bioenergetic signature at 1 month of age, well before overt amyloid pathology. While the observations herein are descriptive in nature and detailed mechanisms have yet to be established, nevertheless, the integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention in AD.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1804332","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:04:03Z","timestamp":1784095443000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pre-plaque glutamatergic hyperexcitability, mitochondrial dysfunction, and dendritic remodeling in the hippocampus of one-month-old 5xFAD mice"],"prefix":"10.3389","volume":"18","author":[{"given":"Amanda R.","family":"Kelley","sequence":"first","affiliation":[{"name":"Linus Pauling Institute, Oregon State University","place":["Corvallis, OR, United States"]},{"name":"Department of Biochemistry and 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