{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:10Z","timestamp":1785428050124,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,16]]},"group-title":"Neuroscience","reference-count":88,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["219556\/Z\/19\/Z"],"award-info":[{"award-number":["219556\/Z\/19\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"name":"William Heart Fund 2026"},{"id":[{"id":"https:\/\/ror.org\/01gghaa40","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,15]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with auditory hypersensitivity, circuit hyperexcitability, and seizures. Whether re-expression of the\n                  <jats:italic>FMR1<\/jats:italic>\n                  gene and encoded Fragile X Messenger Ribonucleoprotein (FMRP) can restore sensory circuit dysfunction remains unclear. Here, we show that a viral AAV-\n                  <jats:italic>FMR1<\/jats:italic>\n                  vector rescues audiogenic seizures in the\n                  <jats:italic>\n                    Fmr1\n                    <jats:sup>\u207b\/y<\/jats:sup>\n                  <\/jats:italic>\n                  mouse model after both neonatal and adult delivery, indicating that auditory circuit dysfunction remains reversible. Local re-expression in the inferior colliculus (IC) is sufficient to reduce seizure susceptibility, identifying this region as a key site of FMRP-dependent circuit regulation. In the IC, Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) profiling reveals impaired induction of sound-evoked translation programs in\n                  <jats:italic>\n                    Fmr1\n                    <jats:sup>-\/y<\/jats:sup>\n                  <\/jats:italic>\n                  neurons, including those regulated by transcription factor\n                  <jats:italic>Npas4<\/jats:italic>\n                  . AAV-\n                  <jats:italic>FMR1<\/jats:italic>\n                  restores a WT-like molecular response and normalizes unbalanced sound-evoked activation of VGLUT2+ excitatory neurons over VGAT+ inhibitory neurons in\n                  <jats:italic>\n                    Fmr1\n                    <jats:sup>-\/y<\/jats:sup>\n                  <\/jats:italic>\n                  IC. Together, these findings indicate altered translation of\n                  <jats:italic>Npas4<\/jats:italic>\n                  in response to sound impairs recruitment of inhibition in the\n                  <jats:italic>\n                    Fmr1\n                    <jats:sup>-\/y<\/jats:sup>\n                  <\/jats:italic>\n                  IC, and this can be reversed with AAV-\n                  <jats:italic>FMR1<\/jats:italic>\n                  administration. Moreover, the rescue of seizures after adult administration of AAV-\n                  <jats:italic>FMR1<\/jats:italic>\n                  supports a gene therapy approach for FXS.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        TRAP-seq reveals impaired activity-driven translation in\n                        <jats:italic>\n                          Fmr1\n                          <jats:sup>-\/y<\/jats:sup>\n                        <\/jats:italic>\n                        inferior colliculus (IC)\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Deficient\n                        <jats:italic>Npas4<\/jats:italic>\n                        induction reduces evoked inhibition in\n                        <jats:italic>\n                          Fmr1\n                          <jats:sup>-\/y<\/jats:sup>\n                        <\/jats:italic>\n                        IC\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        AAV9-\n                        <jats:italic>FMR1<\/jats:italic>\n                        gene therapy normalizes translation and excitatory\/inhibitory balance in\n                        <jats:italic>\n                          Fmr1\n                          <jats:sup>-\/y<\/jats:sup>\n                        <\/jats:italic>\n                        IC\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        AAV9-\n                        <jats:italic>FMR1<\/jats:italic>\n                        gene therapy prevents audiogenic seizures in\n                        <jats:italic>\n                          Fmr1\n                          <jats:sup>-\/y<\/jats:sup>\n                        <\/jats:italic>\n                        mice when administered neonatally or in adulthood\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.12.731901","type":"posted-content","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T08:55:10Z","timestamp":1781600110000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>FMR1<\/i>\n                  gene therapy restores activity-driven inhibition and prevents audiogenic seizures in\n                  <i>\n                    Fmr1\n                    <sup>-\/y<\/sup>\n                  <\/i>\n                  mice"],"prefix":"10.64898","author":[{"given":"Beatriz","family":"Maio","sequence":"first","affiliation":[{"name":"Rosamund Stone Zander and Hansjoerg Wyss Translational Neuroscience Center, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA, USA"},{"name":"Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Singh","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander and Hansjoerg Wyss Translational Neuroscience Center, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA, USA"},{"name":"Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Hector","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Gadalla","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Selfridge","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, University of Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Aria","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander and Hansjoerg Wyss Translational Neuroscience Center, Boston Children\u2019s Hospital, 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