{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T21:53:31Z","timestamp":1785707611239,"version":"3.56.0"},"reference-count":90,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS086329"],"award-info":[{"award-number":["R01 NS086329"]}],"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":["NS111980 (A.B.)"],"award-info":[{"award-number":["NS111980 (A.B.)"]}],"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":["F32 HD095567 (L.H.N.)"],"award-info":[{"award-number":["F32 HD095567 (L.H.N.)"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001454","name":"American Epilepsy Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001454","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Yale Brown Coxe Postdoctoral Fellowship (L.H.N.) and Swebilius Foundation Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.<\/jats:p>","DOI":"10.1093\/brain\/awab390","type":"journal-article","created":{"date-parts":[[2021,10,15]],"date-time":"2021-10-15T20:23:17Z","timestamp":1634329397000},"page":"1310-1325","source":"Crossref","is-referenced-by-count":34,"title":["Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy"],"prefix":"10.1093","volume":"145","author":[{"given":"Lena H","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travorn","family":"Mahadeo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany V","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather A","family":"Born","sequence":"additional","affiliation":[{"name":"Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E","family":"Anderson","sequence":"additional","affiliation":[{"name":"Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4463-7164","authenticated-orcid":false,"given":"Ang\u00e9lique","family":"Bordey","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"issue":"4","key":"2022052416122187200_awab390-B1","doi-asserted-by":"crossref","first-page":"a022442-1","DOI":"10.1101\/cshperspect.a022442","article-title":"mTOR signaling in epilepsy: Insights from malformations of cortical development","volume":"5","author":"Crino","year":"2015","journal-title":"Cold Spring Harb Perspect Med."},{"issue":"Pt 1","key":"2022052416122187200_awab390-B2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1046\/j.1469-1809.2003.00012.x","article-title":"Tuberous sclerosis: From tubers to mTOR","volume":"67","author":"Kwiatkowski","year":"2003","journal-title":"Ann Hum Genet"},{"issue":"1","key":"2022052416122187200_awab390-B3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/nan.12463","article-title":"Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy","volume":"44","author":"Marsan","year":"2018","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"3","key":"2022052416122187200_awab390-B4","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/joa.12956","article-title":"New insights into a spectrum of developmental malformations related to mTOR dysregulations: Challenges and perspectives","volume":"235","author":"Muhlebner","year":"2019","journal-title":"J Anat"},{"key":"2022052416122187200_awab390-B5","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.neuroscience.2013.07.037","article-title":"Focal malformations of cortical development: New vistas for molecular pathogenesis","volume":"252","author":"Lim","year":"2013","journal-title":"Neuroscience."},{"issue":"2","key":"2022052416122187200_awab390-B6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s40263-014-0223-x","article-title":"mTOR inhibition in epilepsy: Rationale and clinical perspectives","volume":"29","author":"Ostendorf","year":"2015","journal-title":"CNS Drugs"},{"key":"2022052416122187200_awab390-B7","doi-asserted-by":"crossref","first-page":"664695","DOI":"10.3389\/fnana.2021.664695","article-title":"Convergent and divergent mechanisms of epileptogenesis in mTORopathies","volume":"15","author":"Nguyen","year":"2021","journal-title":"Front Neuroanat"},{"issue":"2","key":"2022052416122187200_awab390-B8","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.neuron.2014.09.034","article-title":"The neurology of mTOR","volume":"84","author":"Lipton","year":"2014","journal-title":"Neuron"},{"issue":"2","key":"2022052416122187200_awab390-B9","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.cell.2017.03.035","article-title":"mTOR signaling in growth, metabolism, and disease","volume":"169","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"2022052416122187200_awab390-B10","doi-asserted-by":"crossref","first-page":"18","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"},{"issue":"10","key":"2022052416122187200_awab390-B11","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1172\/JCI127032","article-title":"Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy","volume":"129","author":"Kim","year":"2019","journal-title":"J Clin Invest"},{"issue":"20","key":"2022052416122187200_awab390-B12","doi-asserted-by":"crossref","first-page":"5746","DOI":"10.1093\/hmg\/ddv295","article-title":"Activating the translational repressor 4E-BP or reducing S6K-GSK3beta activity prevents accelerated axon growth induced by hyperactive mTOR in vivo","volume":"24","author":"Gong","year":"2015","journal-title":"Hum Mol Genet."},{"issue":"40","key":"2022052416122187200_awab390-B13","doi-asserted-by":"crossref","first-page":"11330","DOI":"10.1073\/pnas.1605740113","article-title":"Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration","volume":"113","author":"Lin","year":"2016","journal-title":"Proc Natl Acad Sci"},{"issue":"570","key":"2022052416122187200_awab390-B14","doi-asserted-by":"crossref","first-page":"eabc1492","DOI":"10.1126\/scitranslmed.abc1492","article-title":"Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice","volume":"12","author":"Hsieh","year":"2020","journal-title":"Sci Transl Med"},{"issue":"1","key":"2022052416122187200_awab390-B15","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1542\/peds.2010-0192","article-title":"Tuberous sclerosis complex: Diagnostic challenges, presenting symptoms, and commonly missed signs","volume":"127","author":"Staley","year":"2011","journal-title":"Pediatrics"},{"issue":"2","key":"2022052416122187200_awab390-B16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.12659\/PJR.882968","article-title":"Focal cortical dysplasia\u2014Review","volume":"77","author":"Kabat","year":"2012","journal-title":"Pol J Radiol"},{"issue":"1","key":"2022052416122187200_awab390-B17","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s13023-018-0870-y","article-title":"Incidence of tuberous sclerosis and age at first diagnosis: New data and emerging trends from a national, prospective surveillance study","volume":"13","author":"Ebrahimi-Fakhari","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"2022052416122187200_awab390-B18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.seizure.2018.04.002","article-title":"Age at epilepsy onset in patients with focal cortical dysplasias, gangliogliomas and dysembryoplastic neuroepithelial tumours","volume":"58","author":"Racz","year":"2018","journal-title":"Seizure."},{"issue":"11","key":"2022052416122187200_awab390-B19","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/s41582-020-0395-6","article-title":"International consensus recommendations on the diagnostic work-up for malformations of cortical development","volume":"16","author":"Oegema","year":"2020","journal-title":"Nat Rev Neurol"},{"issue":"7025","key":"2022052416122187200_awab390-B20","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature03205","article-title":"Regulation of cap-dependent translation by eIF4E inhibitory proteins","volume":"433","author":"Richter","year":"2005","journal-title":"Nature"},{"issue":"5","key":"2022052416122187200_awab390-B21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrm2672","article-title":"Molecular mechanisms of mTOR-mediated translational control","volume":"10","author":"Ma","year":"2009","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"22","key":"2022052416122187200_awab390-B22","doi-asserted-by":"crossref","first-page":"19667","DOI":"10.1074\/jbc.M301142200","article-title":"Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mammalian target of rapamycin and for recognition by raptor","volume":"278","author":"Choi","year":"2003","journal-title":"J Biol Chem"},{"issue":"10","key":"2022052416122187200_awab390-B23","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0960-9822(03)00329-4","article-title":"TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function","volume":"13","author":"Schalm","year":"2003","journal-title":"Curr Biol"},{"issue":"50","key":"2022052416122187200_awab390-B24","doi-asserted-by":"crossref","first-page":"35053","DOI":"10.1074\/jbc.M805822200","article-title":"RalA functions as an indispensable signal mediator for the nutrient-sensing system","volume":"283","author":"Maehama","year":"2008","journal-title":"J Biol Chem."},{"key":"2022052416122187200_awab390-B25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1749-8104-7-26","article-title":"Rapid genetic targeting of pial surface neural progenitors and immature neurons by neonatal electroporation","volume":"7","author":"Breunig","year":"2012","journal-title":"Neural Dev"},{"issue":"5","key":"2022052416122187200_awab390-B26","doi-asserted-by":"crossref","first-page":"e38174","DOI":"10.1371\/journal.pone.0038174","article-title":"miR-132 enhances dendritic morphogenesis, spine density, synaptic integration, and survival of newborn olfactory bulb neurons","volume":"7","author":"Pathania","year":"2012","journal-title":"PLoS One"},{"key":"2022052416122187200_awab390-B27","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fncel.2016.00074","article-title":"Reduced hyperpolarization-activated current contributes to enhanced intrinsic excitability in cultured hippocampal neurons from PrP(\u2013\/\u2013) Mice","volume":"10","author":"Fan","year":"2016","journal-title":"Front Cell Neurosci"},{"issue":"8","key":"2022052416122187200_awab390-B28","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1523\/JNEUROSCI.20-08-02994.2000","article-title":"The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice","volume":"20","author":"Thoby-Brisson","year":"2000","journal-title":"J Neurosci."},{"issue":"5","key":"2022052416122187200_awab390-B29","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nn.2307","article-title":"HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K(+) channels","volume":"12","author":"George","year":"2009","journal-title":"Nat Neurosci"},{"issue":"14","key":"2022052416122187200_awab390-B30","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1523\/JNEUROSCI.2260-18.2019","article-title":"mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical dysplasia","volume":"39","author":"Nguyen","year":"2019","journal-title":"J Neurosci"},{"issue":"9","key":"2022052416122187200_awab390-B31","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/S1474-4422(09)70201-7","article-title":"Focal cortical dysplasia type II: Biological features and clinical perspectives","volume":"8","author":"Sisodiya","year":"2009","journal-title":"Lancet Neurol"},{"issue":"1","key":"2022052416122187200_awab390-B32","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/j.1528-1167.2010.02777.x","article-title":"The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission","volume":"52","author":"Blumcke","year":"2011","journal-title":"Epilepsia"},{"key":"2022052416122187200_awab390-B33","doi-asserted-by":"crossref","first-page":"NA","DOI":"10.1186\/s42047-018-0024-5","article-title":"Identification and immunophenotype of abnormal cells present in focal cortical dysplasia type IIb. Report","volume":"1","author":"Sousa","year":"2018","journal-title":"Surg Exp Pathol"},{"key":"2022052416122187200_awab390-B34","doi-asserted-by":"crossref","first-page":"11753","DOI":"10.1038\/ncomms11753","article-title":"Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement","volume":"7","author":"Hsieh","year":"2016","journal-title":"Nat Commun"},{"issue":"531","key":"2022052416122187200_awab390-B35","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aay0289","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."},{"issue":"Pt 1","key":"2022052416122187200_awab390-B36","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1469-7793.1999.125af.x","article-title":"Contribution of the hyperpolarization-activated current to the resting membrane potential of rat nodose sensory neurons","volume":"514","author":"Doan","year":"1999","journal-title":"J Physiol"},{"issue":"Pt 1","key":"2022052416122187200_awab390-B37","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1113\/jphysiol.2003.047191","article-title":"Role of the hyperpolarization-activated cation current (Ih) in pacemaker activity in area postrema neurons of rat brain slices","volume":"552","author":"Funahashi","year":"2003","journal-title":"J Physiol"},{"key":"2022052416122187200_awab390-B38","doi-asserted-by":"crossref","first-page":"619747","DOI":"10.1155\/2012\/619747","article-title":"The role of HCN channels on membrane excitability in the nervous system","volume":"2012","author":"Kase","year":"2012","journal-title":"J Signal Transduct"},{"issue":"3","key":"2022052416122187200_awab390-B39","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s004240050653","article-title":"A hyperpolarization-activated cation current (Ih) contributes to resting membrane potential in rat superior cervical sympathetic neurones","volume":"436","author":"Lamas","year":"1998","journal-title":"Pflugers Arch"},{"issue":"1","key":"2022052416122187200_awab390-B40","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1152\/jn.2001.86.1.261","article-title":"Contribution of the hyperpolarization-activated current (I(h)) to membrane potential and GABA release in hippocampal interneurons","volume":"86","author":"Lupica","year":"2001","journal-title":"J Neurophysiol"},{"issue":"1","key":"2022052416122187200_awab390-B41","doi-asserted-by":"crossref","first-page":"5037","DOI":"10.1038\/s41598-019-41661-9","article-title":"Early postnatal development of pyramidal neurons across layers of the mouse medial prefrontal cortex","volume":"9","author":"Kroon","year":"2019","journal-title":"Sci Rep"},{"issue":"3","key":"2022052416122187200_awab390-B42","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/cne.11039","article-title":"Immunohistochemical localization of Ih channel subunits, HCN1\u20134, in the rat brain","volume":"471","author":"Notomi","year":"2004","journal-title":"J Comp Neurol"},{"key":"2022052416122187200_awab390-B43","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3389\/fnmol.2019.00211","article-title":"Using a multiplex nucleic acid in situ hybridization technique to determine HCN4 mRNA expression in the adult rodent brain","volume":"12","author":"Oyrer","year":"2019","journal-title":"Front Mol Neurosci"},{"issue":"2","key":"2022052416122187200_awab390-B44","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1109\/TAU.1967.1161901","article-title":"The use of fast fourier transform for the estimation of power spectra: A method based on time averaging over short, modified periodograms","volume":"15","author":"Welch","year":"1967","journal-title":"IEEE Trans Audio Electroacoust"},{"issue":"4","key":"2022052416122187200_awab390-B45","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrn1650","article-title":"Normal and pathological oscillatory communication in the brain","volume":"6","author":"Schnitzler","year":"2005","journal-title":"Nat Rev Neurosci."},{"key":"2022052416122187200_awab390-B46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/978-981-13-0908-3_3","volume-title":"Computational EEG analysis: Methods and applications","author":"Kim","year":"2018"},{"issue":"4","key":"2022052416122187200_awab390-B47","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/ana.20211","article-title":"mTOR cascade activation distinguishes tubers from focal cortical dysplasia","volume":"56","author":"Baybis","year":"2004","journal-title":"Ann Neurol"},{"key":"2022052416122187200_awab390-B48","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1749-6632.2009.05117.x","article-title":"The tuberous sclerosis complex","volume":"1184","author":"Orlova","year":"2010","journal-title":"Ann N Y Acad Sci"},{"issue":"5","key":"2022052416122187200_awab390-B49","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.ajpath.2017.01.015","article-title":"Pathologic active mTOR mutation in brain malformation with intractable epilepsy leads to cell-autonomous migration delay","volume":"187","author":"Hanai","year":"2017","journal-title":"Am J Pathol"},{"issue":"5","key":"2022052416122187200_awab390-B50","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.celrep.2014.04.048","article-title":"Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative diseases","volume":"7","author":"Kassai","year":"2014","journal-title":"Cell Rep"},{"issue":"7","key":"2022052416122187200_awab390-B51","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1002\/acn3.50829","article-title":"Effects of antiepileptic drugs in a new TSC\/mTOR-dependent epilepsy mouse model","volume":"6","author":"Koene","year":"2019","journal-title":"Ann Clin Transl Neur"},{"issue":"22","key":"2022052416122187200_awab390-B52","doi-asserted-by":"crossref","first-page":"10804","DOI":"10.1158\/0008-5472.CAN-07-2310","article-title":"Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells","volume":"67","author":"Dowling","year":"2007","journal-title":"Cancer Res"},{"issue":"6","key":"2022052416122187200_awab390-B53","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/CS20110386","article-title":"Cellular and molecular mechanisms of metformin: An overview","volume":"122","author":"Viollet","year":"2012","journal-title":"Clin Sci (Lond)"},{"issue":"6","key":"2022052416122187200_awab390-B54","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nm.4335","article-title":"Metformin ameliorates core deficits in a mouse model of fragile X syndrome","volume":"23","author":"Gantois","year":"2017","journal-title":"Nat Med"},{"issue":"1","key":"2022052416122187200_awab390-B55","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.stem.2012.03.016","article-title":"Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation","volume":"11","author":"Wang","year":"2012","journal-title":"Cell Stem Cell"},{"issue":"18","key":"2022052416122187200_awab390-B56","doi-asserted-by":"crossref","first-page":"17845","DOI":"10.18632\/aging.103693","article-title":"Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis","volume":"12","author":"Zhu","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"2022052416122187200_awab390-B57","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.taap.2016.03.004","article-title":"Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system","volume":"298","author":"Ismaiel","year":"2016","journal-title":"Toxicol Appl Pharmacol"},{"issue":"1","key":"2022052416122187200_awab390-B58","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s12035-014-8866-7","article-title":"Chronic metformin preconditioning provides neuroprotection via suppression of NF-kappaB-mediated inflammatory pathway in rats with permanent cerebral ischemia","volume":"52","author":"Zhu","year":"2015","journal-title":"Mol Neurobiol"},{"issue":"7","key":"2022052416122187200_awab390-B59","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/nm.4345","article-title":"Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug","volume":"23","author":"Wu","year":"2017","journal-title":"Nat Med"},{"issue":"2","key":"2022052416122187200_awab390-B60","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abb1703","article-title":"Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin","volume":"7","author":"Cheah","year":"2021","journal-title":"Sci Adv"},{"issue":"10","key":"2022052416122187200_awab390-B61","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrd.2018.158","article-title":"Gene therapy for neurological disorders: Progress and prospects","volume":"17","author":"Deverman","year":"2018","journal-title":"Nat Rev Drug Discov"},{"issue":"2","key":"2022052416122187200_awab390-B62","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/jnc.15168","article-title":"Recent advances in gene therapy for neurodevelopmental disorders with epilepsy","volume":"157","author":"Turner","year":"2021","journal-title":"J Neurochem"},{"issue":"11","key":"2022052416122187200_awab390-B63","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrn3586","article-title":"Molecular logic of neocortical projection neuron specification, development and diversity","volume":"14","author":"Greig","year":"2013","journal-title":"Nat Rev Neurosci"},{"key":"2022052416122187200_awab390-B64","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pneurobio.2019.01.003","article-title":"Precision in the development of neocortical architecture: From progenitors to cortical networks","volume":"175","author":"Kast","year":"2019","journal-title":"Prog Neurobiol"},{"issue":"6","key":"2022052416122187200_awab390-B65","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1172\/JCI99384","article-title":"Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy","volume":"128","author":"Ribierre","year":"2018","journal-title":"J Clin Invest"},{"key":"2022052416122187200_awab390-B66","doi-asserted-by":"publisher","DOI":"10.1101\/2020.07.08.189399","article-title":"RHEB\/mTOR-hyperactivity causing cortical malformations drives seizures through increased axonal connectivity","author":"Onori","journal-title":"bioRxiv"},{"issue":"6","key":"2022052416122187200_awab390-B67","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1152\/jn.00523.2019","article-title":"BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons","volume":"123","author":"Goz","year":"2020","journal-title":"J Neurophysiol"},{"issue":"2","key":"2022052416122187200_awab390-B68","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/ana.26149","article-title":"Non-cell autonomous epileptogenesis in focal cortical dysplasia","volume":"90","author":"Koh","year":"2021","journal-title":"Ann Neurol"},{"issue":"4","key":"2022052416122187200_awab390-B69","doi-asserted-by":"crossref","first-page":"345","DOI":"10.31887\/DCNS.2012.14.4\/gbuzsaki","article-title":"Brain rhythms and neural syntax: Implications for efficient coding of cognitive content and neuropsychiatric disease","volume":"14","author":"Buzsaki","year":"2012","journal-title":"Dialogues Clin Neurosci"},{"issue":"2B","key":"2022052416122187200_awab390-B70","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1590\/S0004-282X2006000300005","article-title":"Quantitative EEG in children with learning disabilities: Analysis of band power","volume":"64","author":"Fonseca","year":"2006","journal-title":"Arq Neuropsiquiatr"},{"issue":"3","key":"2022052416122187200_awab390-B71","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1590\/S1980-57642009DN30300004","article-title":"The clinical use of quantitative EEG in cognitive disorders","volume":"3","author":"Kanda","year":"2009","journal-title":"Dement Neuropsychol."},{"key":"2022052416122187200_awab390-B72","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ijpsycho.2016.04.004","article-title":"The quantified EEG characteristics of responders and non-responders to long-term treatment with atomoxetine in children with attention deficit hyperactivity disorders","volume":"104","author":"Chiarenza","year":"2016","journal-title":"Int J Psychophysiol"},{"issue":"10","key":"2022052416122187200_awab390-B73","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1136\/jnnp-2016-313501","article-title":"Quantitative EEG parameters correlate with the progression of human prion diseases","volume":"87","author":"Franko","year":"2016","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"17","key":"2022052416122187200_awab390-B74","article-title":"Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: A parallel mouse and human analysis","volume":"9","author":"Sidorov","year":"2017","journal-title":"J Neurodev Disord"},{"issue":"1","key":"2022052416122187200_awab390-B75","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s11689-019-9275-z","article-title":"Electroencephalographic spectral power as a marker of cortical function and disease severity in girls with Rett syndrome","volume":"11","author":"Roche","year":"2019","journal-title":"J Neurodev Disord"},{"key":"2022052416122187200_awab390-B76","doi-asserted-by":"publisher","DOI":"10.1177\/1550059420973095","article-title":"Quantitative EEG Analysis in Angelman Syndrome: Candidate method for assessing therapeutics","author":"Martinez","year":"2020","journal-title":"Clin EEG Neurosci"},{"issue":"9","key":"2022052416122187200_awab390-B77","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1016\/j.eplepsyres.2014.09.006","article-title":"Abnormal functional brain network in epilepsy patients with focal cortical dysplasia","volume":"108","author":"Jeong","year":"2014","journal-title":"Epilepsy Res"},{"issue":"8","key":"2022052416122187200_awab390-B78","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1016\/j.clinph.2014.10.010","article-title":"Focal cortical dysplasia alters electrophysiological cortical hubs in the resting-state","volume":"126","author":"Jin","year":"2015","journal-title":"Clin Neurophysiol"},{"issue":"3","key":"2022052416122187200_awab390-B79","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.ijpsycho.2008.07.001","article-title":"EEG in adults with attention-deficit\/hyperactivity disorder","volume":"70","author":"Clarke","year":"2008","journal-title":"Int J Psychophysiol"},{"issue":"2-3","key":"2022052416122187200_awab390-B80","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0165-1781(01)00277-3","article-title":"Excess beta activity in children with attention-deficit\/hyperactivity disorder: An atypical electrophysiological group","volume":"103","author":"Clarke","year":"2001","journal-title":"Psychiatry Res"},{"issue":"5","key":"2022052416122187200_awab390-B81","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1053\/smrv.2001.0151","article-title":"Beta EEG activity and insomnia","volume":"5","author":"Perlis","year":"2001","journal-title":"Sleep Med Rev."},{"issue":"2","key":"2022052416122187200_awab390-B82","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.conb.2010.02.015","article-title":"Beta-band oscillations\u2013Signalling the status quo?","volume":"20","author":"Engel","year":"2010","journal-title":"Curr Opin Neurobiol"},{"issue":"1","key":"2022052416122187200_awab390-B83","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1365-2788.1993.tb00868.x","article-title":"Development, behaviour and seizures in 300 cases of tuberous sclerosis","volume":"37","author":"Hunt","year":"2008","journal-title":"J Intellect Disabil Res"},{"issue":"2","key":"2022052416122187200_awab390-B84","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.pedhc.2018.07.004","article-title":"Sleep and behavior problems in children with epilepsy","volume":"33","author":"Tsai","year":"2019","journal-title":"J Pediatr Health Care"},{"issue":"2","key":"2022052416122187200_awab390-B85","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/j.1469-8749.1994.tb11819.x","article-title":"Sleep disorder and epilepsy in children with tuberous sclerosis: A questionnaire-based study","volume":"36","author":"Hunt","year":"1994","journal-title":"Dev Med Child Neurol. Feb"},{"issue":"1","key":"2022052416122187200_awab390-B86","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0387-7604(94)00118-H","article-title":"Sleep disorders in tuberous sclerosis: A polysomnographic study","volume":"17","author":"Bruni","year":"1995","journal-title":"Brain Dev"},{"key":"2022052416122187200_awab390-B87","doi-asserted-by":"crossref","first-page":"104615","DOI":"10.1016\/j.nbd.2019.104615","article-title":"Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex","volume":"134","author":"Zhang","year":"2020","journal-title":"Neurobiol Dis"},{"issue":"1","key":"2022052416122187200_awab390-B88","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s12035-020-02086-y","article-title":"GABAergic interneuron and neurotransmission are mTOR-dependently disturbed in experimental focal cortical dysplasia","volume":"58","author":"Zhong","year":"2021","journal-title":"Mol Neurobiol"},{"issue":"20","key":"2022052416122187200_awab390-B89","first-page":"3601","article-title":"Tracking and transforming neocortical progenitors by CRISPR\/Cas9 gene targeting and piggyBac transposase lineage labeling","volume":"142","author":"Chen","year":"2015","journal-title":"Development."},{"issue":"15","key":"2022052416122187200_awab390-B90","doi-asserted-by":"crossref","first-page":"e2025522118","DOI":"10.1073\/pnas.2025522118","article-title":"4E-BP2-dependent translation in parvalbumin neurons controls epileptic seizure threshold","volume":"118","author":"Sharma","year":"2021","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awab390\/43022975\/awab390.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/4\/1310\/43811949\/awab390.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/4\/1310\/43811949\/awab390.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T12:19:49Z","timestamp":1653394789000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/145\/4\/1310\/6440037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":90,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,11,25]]},"published-print":{"date-parts":[[2022,5,24]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awab390","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.04.445850","asserted-by":"object"}]},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,4,1]]},"published":{"date-parts":[[2021,11,25]]}}}