{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:13:03Z","timestamp":1792714383729,"version":"4.5.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":51,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"NIH National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01 NS052819"],"award-info":[{"award-number":["R01 NS052819"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"NIH National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["R01 DA029122"],"award-info":[{"award-number":["R01 DA029122"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH National Heart, Lung and Blood Institute","award":["R01 HL112918"],"award-info":[{"award-number":["R01 HL112918"]}]},{"name":"NIH National Heart, Lung and Blood Institute","award":["R01 HL122967"],"award-info":[{"award-number":["R01 HL122967"]}]},{"DOI":"10.13039\/100000025","name":"NIH National Institute of Mental Health","doi-asserted-by":"crossref","award":["R01 MH118934"],"award-info":[{"award-number":["R01 MH118934"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"crossref","award":["SFARI Explorer Award # 349984"],"award-info":[{"award-number":["SFARI Explorer Award # 349984"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"NIH National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["T32 DA039080"],"award-info":[{"award-number":["T32 DA039080"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,9]]},"abstract":"<jats:p>\n                    <jats:italic>SCN2A<\/jats:italic>\n                    , encoding the neuronal voltage-gated Na\n                    <jats:sup>+<\/jats:sup>\n                    channel Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in\n                    <jats:italic>SCN2A<\/jats:italic>\n                    are loss-of-function mutations, but studies examining how such mutations affect neuronal function and whether\n                    <jats:italic>Scn2a<\/jats:italic>\n                    mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant\n                    <jats:italic>Scn2a<\/jats:italic>\n                    mouse model (\n                    <jats:italic>Scn2a<\/jats:italic>\n                    <jats:sup>\u03941898\/+<\/jats:sup>\n                    <jats:italic\/>\n                    ) by CRISPR that eliminates the Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2 channel\u2019s distal intracellular C-terminal domain, and we analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in WT and\n                    <jats:italic>Scn2a<\/jats:italic>\n                    <jats:sup>\u03941898\/+<\/jats:sup>\n                    <jats:italic\/>\n                    mice and correlated behaviors with clinical data obtained in human subjects with\n                    <jats:italic>SCN2A<\/jats:italic>\n                    variants. Expression of the Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2 mutant in a heterologous expression system revealed decreased Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2 channel function, and cultured pyramidal neurons isolated from\n                    <jats:italic>Scn2a<\/jats:italic>\n                    <jats:sup>\u03941898\/+<\/jats:sup>\n                    <jats:italic\/>\n                    forebrain showed correspondingly reduced voltage-gated Na\n                    <jats:sup>+<\/jats:sup>\n                    channel currents without compensation from other CNS voltage-gated Na\n                    <jats:sup>+<\/jats:sup>\n                    channels. Na\n                    <jats:sup>+<\/jats:sup>\n                    currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na\n                    <jats:sup>+<\/jats:sup>\n                    channel currents,\n                    <jats:italic>Scn2a<\/jats:italic>\n                    <jats:sup>\u03941898\/+<\/jats:sup>\n                    <jats:italic\/>\n                    pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices.\n                    <jats:italic>Scn2a<\/jats:italic>\n                    <jats:sup>\u03941898\/+<\/jats:sup>\n                    <jats:italic\/>\n                    mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function\n                    <jats:italic>SCN2A<\/jats:italic>\n                    variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a\n                    <jats:italic>SCN2A<\/jats:italic>\n                    loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.150698","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T12:02:38Z","timestamp":1624363358000},"source":"Crossref","is-referenced-by-count":22,"title":["Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors"],"prefix":"10.1172","volume":"6","author":[{"given":"Hong-Gang","family":"Wang","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7273-7392","authenticated-orcid":true,"given":"Charlotte C.","family":"Bavley","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, and"},{"name":"Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anfei","family":"Li","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca M.","family":"Jones","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, Center for Autism and the Developing Brain, White Plains, New York, USA."},{"name":"Weill Cornell Autism Research Program and"},{"name":"Sackler Institute for Developmental Psychobiology, Department of Psychiatry, Weill Cornell Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Hackett","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yared","family":"Bayleyen","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7108-9650","authenticated-orcid":true,"given":"Francis S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, and"},{"name":"Weill Cornell Autism Research Program and"},{"name":"Sackler Institute for Developmental Psychobiology, Department of Psychiatry, Weill Cornell Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali M.","family":"Rajadhyaksha","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, and"},{"name":"Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA."},{"name":"Weill Cornell Autism Research Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-0289","authenticated-orcid":true,"given":"Geoffrey S.","family":"Pitt","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute,"},{"name":"Weill Cornell Autism Research Program and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.08.013"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00265-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-06-02306.2003"},{"key":"B4","article-title":"Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models","volume":"2","author":"Gatto","year":"2010","journal-title":"Front Synaptic Neurosci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1227764"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature10945"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3792"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4598"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx054"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2017.01.009"},{"key":"B11","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2019.00145","article-title":"Scn2a haploinsufficiency in mice suppresses hippocampal neuronal excitability, excitatory synaptic drive, and long-term potentiation, and spatial learning and memory","volume":"12","author":"Shin","year":"2019","journal-title":"Front Mol Neurosci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.037"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0163-8"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-019-0265-5"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-49392-7"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.07.033"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1034\/j.1601-183X.2003.00037.x"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201611721"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201912434"},{"issue":"6","key":"B20","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1016\/S0006-3495(00)76829-9","article-title":"Neuronal death and perinatal lethality in voltage-gated sodium channel alpha(II)-deficient mice","volume":"78","author":"Planells-Cases","year":"2000","journal-title":"Biophys J"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-018-0099-2"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2851"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-1848.2004.00076.x"},{"key":"B24","article-title":"Automated three-chambered social approach task for mice","volume":"Chapter 8","author":"Yang","year":"2011","journal-title":"Curr Protoc Neurosci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2018.03.011"},{"key":"B26"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005592401947"},{"issue":"Suppl 1","key":"B28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1162\/089892900562002","article-title":"VI. Genome structure and cognitive map of Williams syndrome","volume":"12","author":"Korenberg","year":"2000","journal-title":"J Cogn Neurosci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/aur.169"},{"issue":"6","key":"B30","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nn.4276","article-title":"Neurobiology of social behavior abnormalities in autism and Williams syndrome","volume":"19","author":"Barak","year":"2016","journal-title":"Nat Neurosci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1825"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.06.027"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.04.042"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-018-0106-x"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-018-5104-4"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.10.003"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2010.10040484"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0679-9"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900003"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu368"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nn1494"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.09.025"},{"key":"B43","article-title":"Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory","volume":"8","author":"Hubner","year":"2014","journal-title":"Front Behav Neurosci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-060909-153238"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.124"},{"key":"B46","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms1064","article-title":"Automated home-cage behavioural phenotyping of mice","volume":"1","author":"Jhuang","year":"2010","journal-title":"Nat Commun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0513-2"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/150698\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:47:06Z","timestamp":1779148026000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/150698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,9]]},"references-count":47,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8,9]]},"published-print":{"date-parts":[[2021,8,9]]}},"alternative-id":["10.1172\/jci.insight.150698"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.150698","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,9]]},"article-number":"e150698"}}