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FXS arises from a trinucleotide repeat expansion in the 5\u2019 UTR of the\n                  <jats:italic>FMR1<\/jats:italic>\n                  gene that silences expression of the RNA-binding protein FMRP. Despite progress in understanding FMRP functions, the identification of effective therapeutic targets has lagged and at present there are no viable treatment options. Here we identify the \u03b17 nicotinic acetylcholine receptor (nAChR) as candidate target for intervention in FXS. In the early postnatal hippocampus of\n                  <jats:italic>Fmr1<\/jats:italic>\n                  knockout (\n                  <jats:italic>Fmr1<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  ) mice, an established pre-clinical model of FXS, the \u03b17 nAChR accessory protein Ly6H is abnormally distributed, showing enrichment at the neuronal surface and mislocalization in dendrites. Ly6H, a GPI-anchored protein, binds \u03b17 nAChRs with high affinity and can limit \u03b17 nAChR surface expression and signaling. We find that \u03b17 nAChR-evoked Ca\n                  <jats:sup>2+<\/jats:sup>\n                  responses are dampened in immature glutamatergic and GABAergic\n                  <jats:italic>Fmr1<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  neurons compared to wild type. Knockdown of endogenous Ly6H in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  neurons is sufficient to rescue dampened \u03b17 nAChR Ca\n                  <jats:sup>2+<\/jats:sup>\n                  responses\n                  <jats:italic>in vitro<\/jats:italic>\n                  , providing evidence of a cell-autonomous role for Ly6H aberrant expression in \u03b17 nAChR hypofunction. In line with intrinsic deficits in \u03b17 nAChR activity in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  neurons,\n                  <jats:italic>in vivo<\/jats:italic>\n                  administration of the \u03b17 nAChR-selective positive allosteric modulator PNU-120596 improved spatial memory and reduced hyperactivity and seizure severity in adolescent\n                  <jats:italic>Fmr1<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  mice. Taken together, our\n                  <jats:italic>in vitro<\/jats:italic>\n                  mechanistic findings and\n                  <jats:italic>in vivo<\/jats:italic>\n                  rescue studies implicate \u03b17 nAChR hypofunction in FXS pathology.\n                <\/jats:p>","DOI":"10.1101\/2024.11.01.621616","type":"posted-content","created":{"date-parts":[[2024,11,3]],"date-time":"2024-11-03T20:20:11Z","timestamp":1730665211000},"source":"Crossref","is-referenced-by-count":0,"title":["Improvement of Behavioral Deficits in a Mouse Model of Fragile X Syndrome by Restoring \u03b17 nAChR Hypofunction Associated with Aberrant Ly6H Expression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-3724","authenticated-orcid":false,"given":"Sarah","family":"Goebel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4209-3834","authenticated-orcid":false,"given":"Dylann","family":"Cordova-Martinez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6647-1102","authenticated-orcid":false,"given":"Vytas K.","family":"Verselis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1765-3246","authenticated-orcid":false,"given":"Anna","family":"Francesconi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025100701001198000_2024.11.01.621616v2.1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36511"},{"key":"2025100701001198000_2024.11.01.621616v2.2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32439"},{"key":"2025100701001198000_2024.11.01.621616v2.3","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2016-1159F"},{"key":"2025100701001198000_2024.11.01.621616v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90397-H"},{"key":"2025100701001198000_2024.11.01.621616v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00432-0"},{"key":"2025100701001198000_2024.11.01.621616v2.6","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.805929"},{"key":"2025100701001198000_2024.11.01.621616v2.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.00089.x"},{"key":"2025100701001198000_2024.11.01.621616v2.8","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2013.00002"},{"key":"2025100701001198000_2024.11.01.621616v2.9","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.273896"},{"key":"2025100701001198000_2024.11.01.621616v2.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0437947100"},{"key":"2025100701001198000_2024.11.01.621616v2.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134246"},{"key":"2025100701001198000_2024.11.01.621616v2.12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6246-11.2012"},{"key":"2025100701001198000_2024.11.01.621616v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2014.06.007"},{"key":"2025100701001198000_2024.11.01.621616v2.14","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2266-07.2007"},{"key":"2025100701001198000_2024.11.01.621616v2.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.07.013"},{"key":"2025100701001198000_2024.11.01.621616v2.16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5269-04.2005"},{"key":"2025100701001198000_2024.11.01.621616v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2006.03.008"},{"key":"2025100701001198000_2024.11.01.621616v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/ng.93"},{"key":"2025100701001198000_2024.11.01.621616v2.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.01.033"},{"key":"2025100701001198000_2024.11.01.621616v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2003.08.006"},{"key":"2025100701001198000_2024.11.01.621616v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.06.023"},{"key":"2025100701001198000_2024.11.01.621616v2.22","doi-asserted-by":"crossref","unstructured":"J. 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