{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T23:45:03Z","timestamp":1778111103527,"version":"3.51.4"},"posted":{"date-parts":[[2023,5,30]]},"group-title":"Neuroscience","reference-count":96,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,5,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Alzheimer\u2019s disease (AD) is a chronic neurodegenerative disorder that is characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in the hippocampus, but less is known about what happens in the medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured the neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at early (3 months) and late (10 months) time points in the 3xTg mouse model of AD pathology. At 3 months of age, prior to the onset of memory impairments, we found early hyperexcitability in MECII stellate and pyramidal cells\u2019 intrinsic properties, but this was balanced by a relative reduction in synaptic excitation (E) compared to inhibition (I), suggesting intact homeostatic mechanisms regulating activity in MECII. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in the synaptic E\/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable and this was further exacerbated by an increased synaptic E\/I ratio. This observed combination of increased intrinsically and synaptically generated excitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this post-symptomatic time point. Together, these data suggest that the breakdown in homeostatic excitability mechanisms in MECII stellate cells may contribute to the emergence of memory deficits in AD.<\/jats:p>","DOI":"10.1101\/2023.05.30.542838","type":"posted-content","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:23:14Z","timestamp":1685492594000},"source":"Crossref","is-referenced-by-count":11,"title":["Progressive excitability changes in the medial entorhinal cortex in the 3xTg mouse model of Alzheimer\u2019s disease pathology"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5170-8488","authenticated-orcid":false,"given":"Lingxuan","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2752-0140","authenticated-orcid":false,"given":"Zo\u00e9","family":"Christenson Wick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren M.","family":"Vetere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nick","family":"Vaughan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Jurkowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelina","family":"Galas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keziah S.","family":"Diego","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Philipsberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-0523","authenticated-orcid":false,"given":"Denise J.","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-6142","authenticated-orcid":false,"given":"Tristan","family":"Shuman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023060114301287000_2023.05.30.542838v1.1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1993.70.1.128"},{"key":"2023060114301287000_2023.05.30.542838v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22559"},{"key":"2023060114301287000_2023.05.30.542838v1.3","doi-asserted-by":"crossref","first-page":"e12873","DOI":"10.1111\/acel.12873","article-title":"Temporal and regional progression of Alzheimer\u2019s disease-like pathology in 3xTg-AD mice","volume":"18","year":"2019","journal-title":"Aging Cell"},{"key":"2023060114301287000_2023.05.30.542838v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.01.040"},{"key":"2023060114301287000_2023.05.30.542838v1.5","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2845-14.2016"},{"key":"2023060114301287000_2023.05.30.542838v1.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2151-15.2016"},{"key":"2023060114301287000_2023.05.30.542838v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2023060114301287000_2023.05.30.542838v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/neu.480260305"},{"key":"2023060114301287000_2023.05.30.542838v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.05.025"},{"key":"2023060114301287000_2023.05.30.542838v1.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2177-05.2005"},{"key":"2023060114301287000_2023.05.30.542838v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00830-9"},{"key":"2023060114301287000_2023.05.30.542838v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206171109"},{"key":"2023060114301287000_2023.05.30.542838v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1162844"},{"key":"2023060114301287000_2023.05.30.542838v1.14","first-page":"1","article-title":"Impairments of neural circuit function in Alzheimer\u2019s disease","volume":"371","year":"2016","journal-title":"Philos Trans R Soc London - 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