{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:09:36Z","timestamp":1779149376766,"version":"3.51.4"},"reference-count":74,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006117","name":"Epilepsiefonds","doi-asserted-by":"crossref","award":["16-09"],"award-info":[{"award-number":["16-09"]}],"id":[{"id":"10.13039\/501100006117","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010573","name":"Stichting Dioraphte","doi-asserted-by":"crossref","award":["n.a."],"award-info":[{"award-number":["n.a."]}],"id":[{"id":"10.13039\/501100010573","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,8]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC), caused by heterozygous mutations in\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    , frequently results in intractable epilepsy. Here, we made use of an inducible\n                    <jats:italic>Tsc1<\/jats:italic>\n                    -knockout mouse model, allowing us to study electrophysiological and molecular changes of\n                    <jats:italic>Tsc1<\/jats:italic>\n                    -induced epileptogenesis over time. We recorded from pyramidal neurons in the hippocampus and somatosensory cortex (L2\/L3) and combined this with an analysis of transcriptome changes during epileptogenesis. Deletion of\n                    <jats:italic>Tsc1<\/jats:italic>\n                    resulted in hippocampus-specific changes in excitability and adaptation, which emerged before seizure onset and progressed over time. All phenotypes were rescued after early treatment with rapamycin, an mTOR inhibitor. Later in epileptogenesis, we observed a hippocampal increase of excitation-to-inhibition ratio. These cellular changes were accompanied by dramatic transcriptional changes, especially after seizure onset. Most of these changes were rescued upon rapamycin treatment. Of the genes encoding ion channels or belonging to the Gene Ontology term action potential, 27 were differentially expressed just before seizure onset, suggesting a potential driving role in epileptogenesis. Our data highlight the complex changes driving epileptogenesis in TSC, including the changed expression of multiple ion channels. Our study emphasizes inhibition of the TSC\/mTOR signaling pathway as a promising therapeutic approach to target epilepsy in patients with TSC.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.150120","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T14:00:50Z","timestamp":1638885650000},"source":"Crossref","is-referenced-by-count":15,"title":["Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6482-9473","authenticated-orcid":true,"given":"Linda M.C.","family":"Koene","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5654-8425","authenticated-orcid":true,"given":"Eva","family":"Niggl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilse","family":"Wallaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Proietti-Onori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-3596","authenticated-orcid":true,"given":"Diana C.","family":"Rotaru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3758-1297","authenticated-orcid":true,"given":"Ype","family":"Elgersma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"issue":"1","key":"B1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1749-6632.1991.tb37754.x","article-title":"Epidemiology of tuberous sclerosis","volume":"615","author":"Osborne","year":"1991","journal-title":"Ann N Y Acad Sci"},{"issue":"7","key":"B2","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1111\/j.1528-1167.2009.02474.x","article-title":"The natural history of epilepsy in tuberous sclerosis complex","volume":"51","author":"Chu-Shore","year":"2010","journal-title":"Epilepsia"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1085-x"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2012.05.004"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12044"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2997"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.004"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1190287"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.03.017"},{"issue":"30","key":"B10","first-page":"4439","volume":"28","author":"Bateup","year":"2008","journal-title":"Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function"},{"key":"B11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms5563","article-title":"Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model","volume":"5","author":"Lozovaya","year":"2014","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-21656-8"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2982"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.02.090"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.11.019"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0642-19.2019"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.09.011"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001279"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50829"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44909"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5540-06.2007"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nn1566"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1283-12.2012"},{"issue":"1","key":"B24","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a005736","article-title":"Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function","volume":"4","author":"Turrigiano","year":"2012","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/0959-4388(94)90098-1"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.05.037"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001627"},{"key":"B28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnmol.2014.00018","article-title":"Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation","volume":"7","author":"LaSarge","year":"2014","journal-title":"Front Mol Neurosci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.08.002"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2260-18.2019"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12463"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2766-06.2006"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1535-7597.2004.42010.x"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13993-7"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.10.026"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2003.02993.x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-06-02218.2003"},{"key":"B38"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-4959(01)00376-1"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.12.042"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201511507"},{"issue":"4","key":"B42","doi-asserted-by":"crossref","first-page":"ENEURO.0267","DOI":"10.1523\/ENEURO.0267-17.2017","article-title":"Heterogeneity in Kv2 channel expression shapes action potential characteristics and firing patterns in CA1 versus CA2 hippocampal pyramidal neurons","volume":"4","author":"Palacio","year":"2017","journal-title":"eNeuro"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2019.09.004"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.02.006"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25809"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25188"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06145-8"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021014-071846"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/1252"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2013.01.011"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S1090-3798(97)80042-6"},{"key":"B52","first-page":"116","article-title":"Epilepsy in boys with Duchenne muscular dystrophy","volume":"3","author":"Etemadifar","year":"2004","journal-title":"J Res Med Sci"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-015-0331-9"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.09.009"},{"issue":"532","key":"B55","first-page":"1","article-title":"Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations","volume":"12","author":"Zhang","year":"2020","journal-title":"Sci Transl Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-23-08736.2000"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.4161\/cam.5.2.14401"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200212200-00033"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-3406-7"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02088-w"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00985-10"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv087"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0083-18.2018"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0425-0"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23943"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw343"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"issue":"d1","key":"B68","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1093\/nar\/gky955","article-title":"GENCODE reference annotation for the human and mouse genomes","volume":"47","author":"Frankish","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.27"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1055"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/75556"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/150120\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:41:09Z","timestamp":1779147669000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/150120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":74,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12,8]]},"published-print":{"date-parts":[[2021,12,8]]}},"alternative-id":["10.1172\/jci.insight.150120"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.150120","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]},"article-number":"e150120"}}