{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:49:26Z","timestamp":1787014166716,"version":"build-2736575974"},"reference-count":33,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,8,5]],"date-time":"2018-08-05T00:00:00Z","timestamp":1533427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009607","name":"McDonnell Center for Systems Neuroscience","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009607","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS056872"],"award-info":[{"award-number":["R01 NS056872"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["S10 RR027552"],"award-info":[{"award-number":["S10 RR027552"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["U54 HD087011"],"award-info":[{"award-number":["U54 HD087011"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Microglial abnormalities have been reported in pathologic specimens from patients with tuberous sclerosis complex (TSC), a genetic disorder characterized by epilepsy, intellectual disability, and autism. However, the pathogenic role of microglia in epilepsy in\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      is poorly understood, particularly whether microglia defects may be a primary contributor to epileptogenesis or are secondary to seizures or simply epiphenomena. In this study, we tested the hypothesis that\n                      <jats:italic>Tsc1<\/jats:italic>\n                      gene inactivation in microglia is sufficient to cause epilepsy in mouse models of\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using a chemokine receptor, Cx3cr1, to target microglia, conventional\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>Cx3cr1\u2010Cre<\/jats:sup>\n                      <jats:styled-content style=\"fixed-case\">CKO<\/jats:styled-content>\n                      (conditional knockout) mice and postnatal\u2010inducible\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>Cx3cr1\u2010Cre<\/jats:sup>\n                      <jats:styled-content style=\"fixed-case\">\n                        <jats:sup>ER<\/jats:sup>\n                        CKO\n                      <\/jats:styled-content>\n                      mice were generated and assessed for molecular and histopathologic evidence of microglial abnormalities, mechanistic target of rapamycin 1 (mTORC1) pathway activation, and epilepsy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>Cx3cr1\u2010Cre<\/jats:sup>\n                      <jats:styled-content style=\"fixed-case\">CKO<\/jats:styled-content>\n                      mice exhibited a high efficiency of microglia\n                      <jats:italic>Tsc1<\/jats:italic>\n                      inactivation,\n                      <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>\n                      1 activation, increased microglial size and number, and robust epilepsy, which were rapamycin\u2010dependent. However, Cre reporter studies demonstrated that constitutive Cx3cr1 expression affected not only microglia, but also a large percentage of cortical neurons, confounding the role of microglia in epileptogenesis in\n                      <jats:italic>Tsc1<\/jats:italic>\n                      <jats:sup>Cx3cr1\u2010Cre<\/jats:sup>\n                      <jats:styled-content style=\"fixed-case\">CKO<\/jats:styled-content>\n                      mice. In contrast, postnatal inactivation of\n                      <jats:italic>Tsc1<\/jats:italic>\n                      utilizing a tamoxifen\u2010inducible Cx3cr1\u2010Cre\n                      <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                      resulted in a more\u2010selective microglia\n                      <jats:italic>Tsc1<\/jats:italic>\n                      inactivation with high efficiency,\n                      <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>\n                      1 activation, and increased microglial size and number, but no documented epilepsy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      Microglia abnormalities may contribute to epileptogenesis in the context of neuronal involvement in\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      mouse models, but selective\n                      <jats:italic>Tsc1<\/jats:italic>\n                      gene inactivation in microglia alone may not be sufficient to cause epilepsy, suggesting that microglia have more supportive roles in the pathogenesis of seizures in\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.14526","type":"journal-article","created":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T03:18:13Z","timestamp":1533611893000},"page":"1796-1806","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex"],"prefix":"10.1111","volume":"59","author":[{"given":"Bo","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan","family":"Beeler","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph L.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue\u2010Shan","family":"Piao","sequence":"additional","affiliation":[{"name":"Department of Neurology and the Hope Center for Neurological Disorders Washington University School of Medicine St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas 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