{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T10:12:21Z","timestamp":1774692741118,"version":"3.50.1"},"posted":{"date-parts":[[2023,4,10]]},"group-title":"Neuroscience","reference-count":63,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type and\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO (\n                  <jats:italic>\n                    Fmr1\n                    <jats:sup>-\/y<\/jats:sup>\n                  <\/jats:italic>\n                  ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice displayed greatly enhanced excitation, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of LLDs did not appear to reflect changes in inhibitory connections onto MCs but rather enhanced spontaneous excitation of external tufted cells (eTCs) that provide feedforward excitation onto MCs within glomeruli. In addition, in a go\/no-go operant discrimination paradigm, we found that\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the higher excitability of MCs in\n                  <jats:italic>Fmr1<\/jats:italic>\n                  KO mice may impair fine odor discrimination by broadening odor tuning curves of MCs and\/or altering synchronized oscillations through changes in transient inhibition.\n                <\/jats:p>\n                <jats:sec id=\"s1\">\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Fragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used\n                    <jats:italic>Fmr1<\/jats:italic>\n                    knockout (KO) mouse model of FXS. Our studies indicate that\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO alters the local excitation\/inhibition balance in the bulb \u2013 similar to what\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO does in other brain circuits \u2013 but through a novel mechanism that involves enhanced feedforward excitatory drive. Furthermore,\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by enhanced neural excitability.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.04.10.536251","type":"posted-content","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T03:15:21Z","timestamp":1681182921000},"source":"Crossref","is-referenced-by-count":5,"title":["Hyperexcitability in the olfactory bulb and impaired fine odor discrimination in the\n                  <i>Fmr1<\/i>\n                  KO mouse model of fragile X syndrome"],"prefix":"10.64898","author":[{"given":"Praveen","family":"Kuruppath","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Xue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederic","family":"Pouille","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shelly T.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1175-1830","authenticated-orcid":false,"given":"Nathan 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