{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:34:50Z","timestamp":1790742890233,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,9,11]],"date-time":"2022-09-11T00:00:00Z","timestamp":1662854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100016308","name":"Bpifrance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016308","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Many early\u2010onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate receptor (NMDA\u2010R) subunits is being disentangled as one of the mechanisms of severe early\u2010onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA\u2010R with slow deactivation kinetic results in increased neuronal excitation and synchronization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Starting from an available GluN2C\/D antagonist, NMDA\u2010R\u2013modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood\u2013brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in <jats:italic>Tsc1<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice brain slices with multielectrode array, and then in vivo at postnatal ages P14\u2013P17, comparable with the usual age at epilepsy onset in human TSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using a double\u2010electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood\u2013brain barrier was selected. Applied in vivo in six <jats:italic>Tsc1<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice at P14\u2013P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal\u2010like discharges stopped on a human brain sample from an infant with epilepsy due to TSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Subunit\u2010selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA\u2010R subunit\u2013mediated transmission.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17396","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T08:20:05Z","timestamp":1661329205000},"page":"2911-2924","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>GluN2C<\/scp> selective inhibition is a target to develop new antiepileptic compounds"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6001-2976","authenticated-orcid":false,"given":"Svetlana","family":"Gataullina","sequence":"first","affiliation":[{"name":"Service D'explorations Fonctionnelles Multidisciplinaires, Centre de m\u00e9decine du sommeil Antoine B\u00e9cl\u00e8re Hospital, APHP, Universit\u00e9 Paris Saclay  Clamart France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Galvani","sequence":"additional","affiliation":[{"name":"AdPueriVitam (APV)  Antony France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Touchet","sequence":"additional","affiliation":[{"name":"L2CM, CNRS UMR 7053 Universit\u00e9 de Lorraine  Nancy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Nous","sequence":"additional","affiliation":[{"name":"Institut de la Vision, UFR Sciences et Technologies  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9ric","family":"Lemaire","sequence":"additional","affiliation":[{"name":"AdPueriVitam (APV)  Antony 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