{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T02:53:12Z","timestamp":1789872792965,"version":"4.0.1"},"reference-count":98,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Public Health, Japan","award":["20FC1043"],"award-info":[{"award-number":["20FC1043"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1\/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and\/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure\/function, and excessive epileptic discharges, further worsening epilepsy and intellectual\/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.<\/jats:p>","DOI":"10.3390\/ijms22136677","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T13:02:10Z","timestamp":1624366930000},"page":"6677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-6221","authenticated-orcid":false,"given":"Masashi","family":"Mizuguchi","sequence":"first","affiliation":[{"name":"Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"},{"name":"Department of Pediatrics, National Rehabilitation Center for Children with Disabilities, Itabashi-ku, Tokyo 173-0037, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Ohsawa","sequence":"additional","affiliation":[{"name":"Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"},{"name":"Department of Pediatrics, National Rehabilitation Center for Children with Disabilities, Itabashi-ku, Tokyo 173-0037, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Kashii","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo 183-0042, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1093\/hmg\/7.6.1053","article-title":"Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products","volume":"7","author":"Nellist","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16409","DOI":"10.1074\/jbc.270.27.16409","article-title":"Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity","volume":"270","author":"Wienecke","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1074\/jbc.272.10.6097","article-title":"The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis","volume":"272","author":"Xiao","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6306","DOI":"10.1038\/sj.onc.1204009","article-title":"The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination","volume":"19","author":"Benvenuto","year":"2000","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13571","DOI":"10.1073\/pnas.202476899","article-title":"Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling","volume":"99","author":"Tee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2015.03.001","article-title":"The S6K protein family in health and disease","volume":"131","author":"Tavares","year":"2015","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/371762a0","article-title":"Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5\u2032-cap function","volume":"371","author":"Pause","year":"1994","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1101\/gad.912401","article-title":"Hierarchical phosphorylation of the translation inhibitor 4E-BP1","volume":"15","author":"Gingras","year":"2001","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.cell.2006.11.046","article-title":"Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G","volume":"128","author":"Moerke","year":"2007","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1093\/hmg\/ddu101","article-title":"Neuronal Tsc1\/2 complex controls autophagy through AMPK-dependent regulation of ULK1","volume":"23","author":"Wertz","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Limanaqi, F., Biagioni, F., Busceti, C.L., Fabrizi, C., Frati, A., and Fornai, F. (2020). mTOR-related cell-clearing systems in epileptic seizures, an update. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051642"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"LiCausi, F., and Hartman, N.W. (2018). Role of mTOR complexes in neurogenesis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051544"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","article-title":"mTOR at the nexus of nutrition, growth, ageing and disease","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev-immunol-020711-075024","article-title":"Regulation of immune responses by mTOR","volume":"30","author":"Powell","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nm1788","article-title":"Reversal of learning deficits in a Tsc2+\/\u2212 mouse model of tuberous sclerosis","volume":"14","author":"Ehninger","year":"2008","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1038\/ncomms2295","article-title":"Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex","volume":"3","author":"Sato","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_19","first-page":"379","article-title":"The mTOR signaling cascade: Paving new roads to cure neurological disease","volume":"12","author":"Crino","year":"2016","journal-title":"Nat. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34","volume":"277","author":"Hermans","year":"1997","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"European Chromosome 16 Tuberous Sclerosis Consortium (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 75, 1305\u20131315.","DOI":"10.1016\/0092-8674(93)90618-Z"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/ng0294-193","article-title":"Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients","volume":"6","author":"Green","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_23","first-page":"400","article-title":"Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions","volume":"59","author":"Henske","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1212\/WNL.0b013e3181e04325","article-title":"Biallelic TSC gene inactivation in tuberous sclerosis complex","volume":"74","author":"Crino","year":"2010","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0140-6736(12)61134-9","article-title":"Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial","volume":"381","author":"Franz","year":"2013","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial","volume":"381","author":"Bissler","year":"2013","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1016\/S0140-6736(16)31419-2","article-title":"Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): A phase 3, randomised, double-blind, placebo-controlled study","volume":"388","author":"French","year":"2016","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.001","article-title":"International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference","volume":"49","author":"Northrup","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gomez, M.R., Sampson, J.R., and Whittemore, V.H. (1999). Definition and criteria for diagnosis. Tuberous Sclerosis Complex, Oxford University Press. [3rd ed.].","DOI":"10.1093\/oso\/9780195122107.001.0001"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gomez, M.R., Sampson, J.R., and Whittemore, V.H. (1999). Natural history of cerebral tuberous sclerosis. Tuberous Sclerosis Complex, Oxford University Press. [3rd ed.].","DOI":"10.1093\/oso\/9780195122107.001.0001"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wataya-Kaneda, M., Tanaka, M., Hamasaki, T., and Katayama, I. (2013). Trends in the prevalence of tuberous sclerosis complex manifestations: An epidemiological study of 166 Japanese patients. PLoS ONE, 8.","DOI":"10.1371\/annotation\/c511ee3c-f91a-4cfe-bad7-6ef58579717e"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1086\/302381","article-title":"Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis","volume":"64","author":"Jones","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1086\/316951","article-title":"Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs","volume":"68","author":"Dabora","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/jhg.2013.3","article-title":"Mutational analysis of TSC1 and TSC2 in Japanese patients with tuberous sclerosis complex revealed higher incidence of TSC1 patients than previously reported","volume":"58","author":"Niida","year":"2013","journal-title":"J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S1474-4422(15)00069-1","article-title":"Neurological and neuropsychiatric aspects of tuberous sclerosis complex","volume":"14","author":"Curatolo","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s004010050746","article-title":"Tuberin immunohistochemistry in brain, kidneys and heart with or without tuberous sclerosis","volume":"94","author":"Mizuguchi","year":"1997","journal-title":"Acta Neuropathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s004010051152","article-title":"Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis","volume":"99","author":"Mizuguchi","year":"2000","journal-title":"Acta Neuropathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S1383-5742(01)00058-8","article-title":"Tuberous sclerosis gene products in proliferation control","volume":"488","author":"Rodman","year":"2001","journal-title":"Mutat. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/s00401-002-0575-z","article-title":"Doublecortin immunoreactivity in giant cells of tuberous sclerosis and focal cortical dysplasia","volume":"104","author":"Mizuguchi","year":"2002","journal-title":"Acta Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ohsawa, M., Kobayashi, T., Okura, H., Igarashi, T., Mizuguchi, M., and Hino, O. (2013). TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054503"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.2353\/ajpath.2008.070958","article-title":"The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake","volume":"172","author":"Jiang","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ccr.2004.06.020","article-title":"Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes","volume":"6","author":"Brugarolas","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1086\/321972","article-title":"Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions","volume":"69","author":"Niida","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s004010050587","article-title":"Tuberous sclerosis-like lesions in epileptogenic human neocortex lack allelic loss at the TSC1 and TSC2 regions","volume":"93","author":"Wolf","year":"1997","journal-title":"Acta Neuropathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00401-003-0778-y","article-title":"Absence of allelic loss in cytomegalic neurons of cortical tuber in the Eker rat model of tuberous sclerosis","volume":"107","author":"Mizuguchi","year":"2004","journal-title":"Acta Neuropathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S0387-7604(01)00304-7","article-title":"Neuropathology of tuberous sclerosis","volume":"23","author":"Mizuguchi","year":"2001","journal-title":"Brain Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/s00246-016-1528-y","article-title":"Accelerated cardiac rhabdomyoma regression with everolimus in infants with tuberous sclerosis complex","volume":"38","author":"Aw","year":"2017","journal-title":"Pediatr. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1001\/jamadermatol.2018.1408","article-title":"Sirolimus gel treatment vs. placebo for facial angiofibromas in patients with tuberous sclerosis complex: A randomized clinical trial","volume":"154","author":"Ohno","year":"2018","journal-title":"JAMA Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1056\/NEJMoa063564","article-title":"Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis","volume":"358","author":"Bissler","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1017\/S0033291702007092","article-title":"Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex","volume":"33","author":"Joinson","year":"2003","journal-title":"Psychol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chu-Shore, C.J., Major, P., Camposano, S., Muzykewicz, D., and Thiele, E.A. (2010). The natural history of epilepsy in tuberous sclerosis complex. Epilepsia, 51.","DOI":"10.1111\/j.1528-1167.2009.02474.x"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"van Eeghen, A.M., Pulsifer, M.B., Merker, V.L., Neumeyer, A.M., van Eeghen, E.E., Thibert, R.L., Cole, A.J., Leigh, F.A., Plotkin, S.R., and Thiele, E.A. (2013). Understanding relationships between autism, intelligence, and epilepsy: A cross-disorder approach. Dev. Med. Child Neurol., 55.","DOI":"10.1111\/dmcn.12044"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1136\/jmg.2003.012757","article-title":"Genotype and psychological phenotype in tuberous sclerosis","volume":"41","author":"Lewis","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s00787-006-0570-3","article-title":"The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC): A postal survey of UK families","volume":"16","author":"Hunt","year":"2007","journal-title":"Eur. Child Adolesc. Psychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.pediatrneurol.2014.10.004","article-title":"Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist","volume":"52","author":"Whittemore","year":"2015","journal-title":"Pediatr. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1741-4520.2006.00134.x","article-title":"Abnormal giant cells in the cerebral lesions of tuberous sclerosis complex","volume":"47","author":"Mizuguchi","year":"2007","journal-title":"Cong. Anom."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Gomez, M.R., Sampson, J.R., and Whittemore, V.H. (1999). Neuropathology. Tuberous Sclerosis Complex, Oxford University Press. [3rd ed.].","DOI":"10.1093\/oso\/9780195122107.001.0001"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"15704","DOI":"10.1523\/JNEUROSCI.2392-12.2012","article-title":"Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis","volume":"32","author":"McMahon","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00401-013-1135-4","article-title":"mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: Evidence from focal cortical dysplasia and tuberous sclerosis","volume":"126","author":"Yasin","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1002\/ana.10648","article-title":"Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model","volume":"54","author":"Wong","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/1531-8249(200101)49:1<67::AID-ANA10>3.0.CO;2-L","article-title":"Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers","volume":"49","author":"White","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/ana.22696","article-title":"Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia","volume":"71","author":"Talos","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1177\/7010.2006.00242","article-title":"Anomalous inhibitory circuits in cortical tubers of human tuberous sclerosis complex associated with refractory epilepsy: Aberrant expression of parvalbumin and calbindin-D28k in dysplastic cortex","volume":"21","author":"Valencia","year":"2006","journal-title":"J. Child Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/ana.21058","article-title":"Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1","volume":"61","author":"Wang","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13041-019-0427-6","article-title":"Hyperexcitability of the local cortical circuit in mouse models of tuberous sclerosis complex","volume":"12","author":"Zhao","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/BF00334458","article-title":"Cortical tubers demonstrate reduced immunoreactivity for synapsin I","volume":"85","author":"Lippa","year":"1993","journal-title":"Acta Neuropathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6842","DOI":"10.1038\/ncomms7842","article-title":"Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex","volume":"6","author":"Sugiura","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.neuron.2014.07.040","article-title":"Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits","volume":"83","author":"Tang","year":"2014","journal-title":"Neuron"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"8862","DOI":"10.1523\/JNEUROSCI.1617-11.2011","article-title":"Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function","volume":"31","author":"Bateup","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nature10658","article-title":"Mutations causing syndromic autism define an axis of synaptic pathophysiology","volume":"480","author":"Auerbach","year":"2011","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.braindev.2008.09.013","article-title":"Recent advances in neurobiology of Tuberous Sclerosis Complex","volume":"31","author":"Napolioni","year":"2009","journal-title":"Brain Dev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1093\/cercor\/bhs135","article-title":"Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders","volume":"23","author":"Lewis","year":"2013","journal-title":"Cereb. Cortex"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1212\/WNL.0b013e318247ca8d","article-title":"Everolimus alters white matter diffusion in tuberous sclerosis complex","volume":"78","author":"Tillema","year":"2012","journal-title":"Neurology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1073\/pnas.90.1.327","article-title":"Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer","volume":"90","author":"Hino","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/S0022-5347(17)37087-8","article-title":"Hereditary renal cell carcinoma in the Eker rat: A rodent familial cancer syndrome","volume":"148","author":"Everitt","year":"1992","journal-title":"J. Urol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng0195-70","article-title":"A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer","volume":"9","author":"Kobayashi","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1093\/jnen\/59.3.188","article-title":"Novel cerebral lesions in the Eker rat model of tuberous sclerosis: Cortical tuber and anaplastic gangliogioma","volume":"59","author":"Mizuguchi","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00401-004-0865-8","article-title":"Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis","volume":"108","author":"Wenzel","year":"2004","journal-title":"Acta Neuropathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1111\/j.0013-9580.2004.23004.x","article-title":"Abnormal cortical cells and astrocytomas in the Eker rat model of tuberous sclerosis complex","volume":"45","author":"Takahashi","year":"2004","journal-title":"Epilepsia"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s00406-016-0703-8","article-title":"mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus","volume":"267","author":"Schneider","year":"2017","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1172\/JCI44909","article-title":"Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice","volume":"121","author":"Feliciano","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1111\/epi.13325","article-title":"Epilepsy in young Tsc1(+\/\u2212) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex","volume":"57","author":"Gataullina","year":"2016","journal-title":"Epilepsia"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/ana.21317","article-title":"Cognitive deficits in Tsc1+\/\u2212 mice in the absence of cerebral lesions and seizures","volume":"62","author":"Goorden","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s10147-017-1224-9","article-title":"Effect of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: An evaluation based on tumor density","volume":"23","author":"Hatano","year":"2018","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.jaad.2017.04.005","article-title":"Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients","volume":"77","author":"Malissen","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.braindev.2018.07.003","article-title":"Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3substudy in Japan","volume":"41","author":"Mizuguchi","year":"2019","journal-title":"Brain Dev."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ejpn.2019.12.023","article-title":"Deciphering the concepts behind \u201cEpileptic encephalopathy\u201d and \u201cDevelopmental and epileptic encephalopathy\u201d","volume":"24","author":"Scheffer","year":"2020","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Talos, D.M., Sun, H., Zhou, X., Fitzgerald, E.C., Jackson, M.C., Klein, P.M., Lan, V.J., Joseph, A., and Jensen, F.E. (2012). The interaction between early life epilepsy and autistic-like behavioral consequences: A role for the mammalian target of rapamycin (mTOR) pathway. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035885"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/epi.12423","article-title":"Therapeutic approach to epileptic encephalopathies","volume":"54","author":"Vigevano","year":"2013","journal-title":"Epilepsia"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1111\/j.1528-1167.2011.02981.x","article-title":"The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway","volume":"52","author":"McDaniel","year":"2011","journal-title":"Epilepsia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1528-1167.2009.02341.x","article-title":"Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies","volume":"51","author":"Wong","year":"2010","journal-title":"Epilepsia"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e142","DOI":"10.1111\/epi.14529","article-title":"Everolimus in infants with tuberous sclerosis complex-related West syndrome: First results from a single-center prospective observational study","volume":"59","author":"Samueli","year":"2018","journal-title":"Epilepsia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s13023-019-1077-6","article-title":"Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age-a multicenter retrospective study","volume":"14","author":"Saffari","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ejpn.2011.03.010","article-title":"Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex","volume":"15","author":"Kotulska","year":"2011","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pediatrneurol.2019.07.008","article-title":"Preventive antiepileptic treatment in tuberous sclerosis complex: Long-term, prospective trial","volume":"101","author":"Jozwiak","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1055\/s-2002-36740","article-title":"Epilepsy surgery outcome in children with focal epilepsy due to tuberous sclerosis complex","volume":"33","author":"Karenfort","year":"2002","journal-title":"Neuropediatrics"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.seizure.2018.06.005","article-title":"Refractory epilepsy in preschool children with tuberous sclerosis complex: Early surgical treatment and outcome","volume":"60","author":"Fohlen","year":"2018","journal-title":"Seizure"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.pediatrneurol.2020.04.002","article-title":"Pilot study of neurodevelopmental impact of early epilepsy surgery in tuberous sclerosis complex","volume":"109","author":"Grayson","year":"2020","journal-title":"Pediatr. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:21:11Z","timestamp":1760163671000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,22]]},"references-count":98,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136677"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136677","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,22]]}}}