{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:35:21Z","timestamp":1776195321695,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T00:00:00Z","timestamp":1507766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS056872"],"award-info":[{"award-number":["R01 NS056872"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007857","name":"Intellectual and Developmental Disabilities Research Center","doi-asserted-by":"publisher","award":["U54 HD087011"],"award-info":[{"award-number":["U54 HD087011"]}],"id":[{"id":"10.13039\/100007857","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Epilepsy is one of the most prominent symptoms of tuberous sclerosis complex (<jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>), a genetic disorder, and may be related to developmental defects resulting from impaired <jats:italic><jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>1<\/jats:italic> or <jats:italic><jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>2<\/jats:italic> gene function in astrocytes and neurons. Inactivation of the <jats:italic>Tsc1<\/jats:italic> gene driven by a glial\u2010fibrillary acidic protein (<jats:styled-content style=\"fixed-case\">GFAP<\/jats:styled-content>) promoter during embryonic brain development leads to widespread pathologic effects on astrocytes and neurons, culminating in severe, progressive epilepsy in mice (<jats:italic>Tsc1<\/jats:italic><jats:styled-content style=\"fixed-case\"><jats:sup>GFAP<\/jats:sup><\/jats:styled-content><jats:sup>\u2010Cre<\/jats:sup> mice). However, the developmental timing and cellular specificity relevant to epileptogenesis in this model has not been well defined. The present study evaluates the effect of postnatal <jats:italic>Tsc1<\/jats:italic> gene inactivation on pathologic features of astrocytes and neurons and development of epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An inducible <jats:italic>Tsc1<\/jats:italic> knock\u2010out mouse was created utilizing a tamoxifen\u2010driven <jats:styled-content style=\"fixed-case\">GFAP<\/jats:styled-content>\u2010Cre<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> line (<jats:italic>Tsc1<\/jats:italic><jats:styled-content style=\"fixed-case\"><jats:sup>GFAP<\/jats:sup><\/jats:styled-content><jats:sup>\u2010Cre<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>ER<\/jats:sup><\/jats:styled-content> mice) with <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>1 reduction induced postnatally at 2 and 6 weeks of age, and compared to conventional <jats:italic>Tsc1<\/jats:italic><jats:styled-content style=\"fixed-case\"><jats:sup>GFAP<\/jats:sup><\/jats:styled-content><jats:sup>\u2010Cre<\/jats:sup> mice with prenatal <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>1 reduction. Western blotting, immunohistochemistry, histology, and video\u2013electroencephalography (<jats:styled-content style=\"fixed-case\">EEG)<\/jats:styled-content> assessed <jats:styled-content style=\"fixed-case\">mechanistic target of rapamycin (mTOR)<\/jats:styled-content> pathway activation, astrogliosis, neuronal organization, and spontaneous seizures, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Tsc1<\/jats:italic> gene inactivation at 2 weeks of age was sufficient to cause astrogliosis and mild epilepsy in <jats:italic>Tsc1<\/jats:italic><jats:styled-content style=\"fixed-case\"><jats:sup>GFAP<\/jats:sup><\/jats:styled-content><jats:sup>\u2010Cre<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>ER<\/jats:sup><\/jats:styled-content> mice, but the phenotype was much less severe than that observed with prenatal <jats:italic>Tsc1<\/jats:italic> gene inactivation in <jats:italic>Tsc1<\/jats:italic><jats:styled-content style=\"fixed-case\"><jats:sup>GFAP<\/jats:sup><\/jats:styled-content><jats:sup>\u2010Cre<\/jats:sup> mice. Both astrocytes and neurons were affected by prenatal and postnatal <jats:italic>Tsc1<\/jats:italic> gene activation to a degree similar to the severity of epilepsy, suggesting that both cellular types may contribute to epileptogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These findings support a model in which the developmental timing of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>1 loss dictates the severity of neuronal and glial abnormalities and resulting epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13923","type":"journal-article","created":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T05:32:50Z","timestamp":1507786370000},"page":"2053-2063","source":"Crossref","is-referenced-by-count":29,"title":["Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age\u2010dependent 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Neurological Disorders Washington University School of Medicine St. Louis Missouri 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