{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:07:02Z","timestamp":1788847622364,"version":"build-2803163510"},"reference-count":55,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"31","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NINDS NS29709"],"award-info":[{"award-number":["NINDS NS29709"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MH131719"],"award-info":[{"award-number":["MH131719"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013113","name":"Stanley Center for Psychiatric Research, Broad Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013113","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013114","name":"Broad Institute of MIT and Harvard","doi-asserted-by":"crossref","award":["ladders to Cures Scientific Accelerator"],"award-info":[{"award-number":["ladders to Cures Scientific Accelerator"]}],"id":[{"id":"10.13039\/100013114","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Blue Bird Circle Foundation"},{"name":"CACNA1A foundation"},{"name":"CACNA1A foundation"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:p>\n                    Childhood absence epilepsy (CAE) is a common genetic epilepsy with a frequently complex polygenic etiology, for which a genetically tractable animal model is lacking. Current anti-seizure medications fail to address the significant neurocognitive and social comorbidities of CAE, highlighting a critical unmet need for comprehensive therapies and a better understanding of the underlying mechanisms. To address this, we developed a digenic mouse model (\n                    <jats:italic toggle=\"yes\">Cacng2<\/jats:italic>\n                    <jats:sup>stargazer\/+<\/jats:sup>\n                    ;\n                    <jats:italic toggle=\"yes\">Cacna1a<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    , hereafter DiG\n                    <jats:sup>stg+Ca1A<\/jats:sup>\n                    ) that mimics human polygenicity. The double mutant mice exhibit both absence seizures and altered social novelty preference. We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiG\n                    <jats:sup>stg+Ca1A<\/jats:sup>\n                    mice but failed to rescue their social deficit. Similarly, deletion of\n                    <jats:italic toggle=\"yes\">Cacna1g<\/jats:italic>\n                    , which encodes the T-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel Ca\n                    <jats:sub>V<\/jats:sub>\n                    3.1, prevented seizure generation but did not ameliorate the social deficit. These findings reveal a dissociation between the T-type current that mediates seizures and the mechanism underlying the social deficits. We further demonstrate that in\n                    <jats:italic toggle=\"yes\">Cacng2<\/jats:italic>\n                    <jats:sup>stargazer\/+<\/jats:sup>\n                    mice, selective deletion of one copy of\n                    <jats:italic toggle=\"yes\">Cacna1a<\/jats:italic>\n                    in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and impaired social behavior. Remarkably, chemogenetic activation of cortical and thalamic PV interneurons using DREADDs not only suppressed seizures but also rescued the impaired social behavior. Together, our results suggest that selective modulation of PV interneuron activity in polygenic absence epilepsy could serve as a promising therapeutic strategy to address both absence seizures, and the often treatment-resistant neurocognitive comorbidities observed in CAE.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec6065","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:58:34Z","timestamp":1785520714000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Parvalbumin interneuron activation rescues both seizures and impaired social novelty in digenic absence epilepsy mice"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1420-2363","authenticated-orcid":true,"given":"Qing-Long","family":"Miao","sequence":"first","affiliation":[{"name":"Blue Bird Circle Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Okoh","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet S.","family":"Asan","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3402-8530","authenticated-orcid":true,"given":"Saifina","family":"Karedia","sequence":"additional","affiliation":[{"name":"Blue Bird Circle Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0767-086X","authenticated-orcid":true,"given":"Jen Q.","family":"Pan","sequence":"additional","affiliation":[{"name":"Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Costa-Mattioli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2887-0839","authenticated-orcid":true,"given":"Jeffrey L.","family":"Noebels","sequence":"additional","affiliation":[{"name":"Blue Bird Circle Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa072"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0902014"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12028"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/archpedi.1997.02170390042008"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.5698\/1535-7511-13.3.135"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-021-00583-9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-63326-2.00012-0"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2022.2072449"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP274696"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-15-06362.2002"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5546-03.2004"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz365"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23913"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.78349"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01096-z"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00967-6"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01175-1"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2024.1359237"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2504-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0607-16.2016"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00156"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5342-10.2011"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2020.08.023"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.04.013"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf7003"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13028"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03956-8"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adt9008"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adn1335"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41744-2"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.044"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.688905"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104610"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.034"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2475"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07991"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.08.036"},{"key":"e_1_3_2_39_2","first-page":"49","article-title":"Block 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