{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:05:02Z","timestamp":1782281102898,"version":"3.54.5"},"posted":{"date-parts":[[2025,8,27]]},"group-title":"Neuroscience","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the\n                  <jats:italic>FMR1<\/jats:italic>\n                  gene. Synaptic and circuit-level abnormalities are well documented in FXS and extensively studied in the\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mouse model. In CA1 hippocampal neurons functional, molecular and structural synaptic changes have been described yet the canonical form of Hebbian CA1 long term potentiation (LTP) remains intact in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior \u201cpriming\u201d activity modulates subsequent synaptic plasticity, was affected in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming, and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO slices, implicating altered SK activity in the exaggerated LTP inhibition in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice. These finding reveal a disrupted coupling between NMDA receptors and SK channels in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice, which alters the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired adaptive hippocampal learning in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    While conventional synaptic plasticity (LTP and LTD) has been extensively examined in\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice, evidence about the integrity of metaplasticity in these mice has been limited. This study provides a characterization of alterations in NMDA receptor mediated metaplasticity in the hippocampus in\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice. The question of whether hippocampal LTP is altered in these mice remains unresolved, and changes in metaplasticity may partly explain the discrepancies across studies. Our findings not only identify novel synaptic phenotypes and their underlying mechanisms in the FXS mouse model, but also highlight potential therapeutic targets for FXS.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.26.672454","type":"posted-content","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T09:40:11Z","timestamp":1756287611000},"source":"Crossref","is-referenced-by-count":0,"title":["Exaggerated NMDA Receptor\u2013Primed Metaplasticity via SK Channel Dysregulation in\n                  <i>Fmr1<\/i>\n                  Knockout Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8786-831X","authenticated-orcid":false,"given":"Toshihiro","family":"Nomura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Morton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anis","family":"Contractor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025083003350485000_2025.08.26.672454v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2356"},{"key":"2025083003350485000_2025.08.26.672454v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(96)80018-X"},{"key":"2025083003350485000_2025.08.26.672454v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-020911-153336"},{"key":"2025083003350485000_2025.08.26.672454v1.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3565-06.2007"},{"key":"2025083003350485000_2025.08.26.672454v1.5","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00449.2010"},{"key":"2025083003350485000_2025.08.26.672454v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.04.009"},{"key":"2025083003350485000_2025.08.26.672454v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.08.033"},{"key":"2025083003350485000_2025.08.26.672454v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2021.06.025"},{"key":"2025083003350485000_2025.08.26.672454v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bht237"},{"key":"2025083003350485000_2025.08.26.672454v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2014.01.002"},{"key":"2025083003350485000_2025.08.26.672454v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.02.002"},{"key":"2025083003350485000_2025.08.26.672454v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2022.102553"},{"key":"2025083003350485000_2025.08.26.672454v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301559"},{"key":"2025083003350485000_2025.08.26.672454v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1063(1998)8:2<160::AID-HIPO8>3.0.CO;2-P"},{"key":"2025083003350485000_2025.08.26.672454v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1840-08.2008"},{"key":"2025083003350485000_2025.08.26.672454v1.16","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.796053"},{"key":"2025083003350485000_2025.08.26.672454v1.17","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1593-18.2018"},{"key":"2025083003350485000_2025.08.26.672454v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960809)64:2<246::AID-AJMG2>3.0.CO;2-S"},{"key":"2025083003350485000_2025.08.26.672454v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.65"},{"key":"2025083003350485000_2025.08.26.672454v1.20","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1496-08.2008"},{"key":"2025083003350485000_2025.08.26.672454v1.21","doi-asserted-by":"publisher","DOI":"10.1126\/science.1346729"},{"key":"2025083003350485000_2025.08.26.672454v1.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.122205699"},{"key":"2025083003350485000_2025.08.26.672454v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(92)90414-3"},{"key":"2025083003350485000_2025.08.26.672454v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20383"},{"key":"2025083003350485000_2025.08.26.672454v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(92)90442-A"},{"key":"2025083003350485000_2025.08.26.672454v1.26","doi-asserted-by":"crossref","unstructured":"Jones SL , To MS , Stuart GJ (2017) Dendritic small conductance calcium-activated potassium channels activated by action potentials suppress EPSPs and gate spike-timing dependent synaptic plasticity. 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