{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:05:50Z","timestamp":1792083950406,"version":"4.4.0"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"43","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,25]]},"abstract":"<jats:p>\n                    Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein,\n                    <jats:italic>retinoic acid induced 1<\/jats:italic>\n                    (\n                    <jats:italic>RAI1<\/jats:italic>\n                    ), causes Smith\u2013Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural\n                    <jats:italic>Rai1<\/jats:italic>\n                    deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in\u00a0vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in\n                    <jats:italic>Rai1<\/jats:italic>\n                    -deficient brains. Deletion of\n                    <jats:italic>Rai1<\/jats:italic>\n                    from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting\n                    <jats:italic>Rai1<\/jats:italic>\n                    from the\n                    <jats:italic>\n                      Emx1\n                      <jats:sup>Cre<\/jats:sup>\n                    <\/jats:italic>\n                    -lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2210122119","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T14:19:12Z","timestamp":1666102752000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Loss of\n                    <i>Rai1<\/i>\n                    enhances hippocampal excitability and epileptogenesis in mouse models of Smith\u2013Magenis syndrome"],"prefix":"10.1073","volume":"119","author":[{"given":"Ya-Ting","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, QC, H3G 1A3, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montr\u00e9al, QC, H3G 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Kowalczyk","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, QC, H3G 1A3, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montr\u00e9al, QC, H3G 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Michelle","family":"Fogerson","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5319-7498","authenticated-orcid":false,"given":"Yu-Ju","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, QC, H3G 1A3, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montr\u00e9al, QC, H3G 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minza","family":"Haque","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, QC, H3G 1A3, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montr\u00e9al, QC, H3G 1A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza L.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305"},{"name":"HHMI, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"DeNardo","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305"},{"name":"HHMI, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Tessier-Lavigne","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Huguenard","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5467-9264","authenticated-orcid":false,"given":"Liqun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305"},{"name":"HHMI, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hsiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, McGill University, QC, H3G 1A3, Canada"},{"name":"Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montr\u00e9al, QC, H3G 1A3, Canada"},{"name":"Department of Biology, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1601-183X.2003.00037.x"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.06.017"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2016.12.036"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.03.017"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.07.018"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.07.033"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab3897"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30275"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320240303"},{"key":"e_1_3_5_10_2","first-page":"1207","article-title":"Molecular analysis of the Smith-Magenis syndrome: A possible contiguous-gene syndrome associated with del(17)(p11.2)","volume":"49","author":"Greenberg F.","year":"1991","unstructured":"F. 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Loss of Rai1 enhances hippocampal excitability and epileptogenesis in mouse models of Smith\u2013Magenis syndrome. Zenodo. https:\/\/zenodo.org\/record\/7140061#.Yzs2Y3bMLEZ. 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