Featured Publications
Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy
Nguyen LH, Xu Y, Mahadeo T, Zhang L, Lin TV, Born HA, Anderson AE, Bordey A. Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy. Brain 2021, 145: 1310-1325. PMID: 34849602, PMCID: PMC9128821, DOI: 10.1093/brain/awab390.Peer-Reviewed Original ResearchConceptsFocal malformationsCortical developmentJuvenile miceCortical spectral activitySpontaneous seizure frequencyIrregular firing patternNovel therapeutic opportunitiesNeuronal cytomegalySeizure frequencyEpilepsy onsetNeuronal abnormalitiesElectrophysiological alterationsIntractable epilepsyNeuronal dysfunctionJuvenile brainMouse modelMTOR pathwayTherapeutic opportunitiesMalformationsFiring patternsEpilepsyAberrant expressionNeurodevelopmental disordersMTOR effectorsMiceEctopic HCN4 expression drives mTOR-dependent epilepsy in mice
Hsieh LS, Wen JH, Nguyen LH, Zhang L, Getz SA, Torres-Reveron J, Wang Y, Spencer DD, Bordey A. Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice. Science Translational Medicine 2020, 12 PMID: 33208499, PMCID: PMC9888000, DOI: 10.1126/scitranslmed.abc1492.Peer-Reviewed Original ResearchConceptsFocal cortical dysplasia type IITuberous sclerosis complexFocal cortical malformationsPyramidal neuronsMouse modelHCN4 expressionCortical pyramidal neuronsOnset of seizuresIntracellular cAMP concentrationSeizure activityCortical malformationsRepetitive firingDiseased neuronsSeizuresAbnormal expressionNeuronsEpilepsyCausative linkSeizure mechanismsCAMP concentrationMechanistic targetHCN4Channel activityPatientsGene therapyConvulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement
Hsieh LS, Wen JH, Claycomb K, Huang Y, Harrsch FA, Naegele JR, Hyder F, Buchanan GF, Bordey A. Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement. Nature Communications 2016, 7: 11753. PMID: 27249187, PMCID: PMC4895394, DOI: 10.1038/ncomms11753.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell MovementCognitive DysfunctionDisease Models, AnimalFemaleGene Expression RegulationGenes, ReporterGreen Fluorescent ProteinsHumansMaleMalformations of Cortical DevelopmentMiceNeuronsPrefrontal CortexSeizuresSignal TransductionSirolimusTOR Serine-Threonine KinasesWhite MatterConceptsFocal cortical dysplasiaCortical dysplasiaType II focal cortical dysplasiaWhite matter heterotopiasLayer 2/3 neuronsLife-long treatmentTonic-clonic seizuresNormal survival rateMedial prefrontal cortexLocal malformationsConvulsive seizuresPharmacoresistant epilepsySeizure activitySeizure generationSeizure occurrenceCommon causeCortical developmentMurine modelNeurocognitive impairmentSurvival rateSeizuresRapamycin withdrawalPrefrontal cortexMTOR activityRapamycin treatment
2023
In Utero Electroporated Neurons for Medium-Throughput Screening of Compounds Regulating Neuron Morphology
Sokolov A, Aurich M, Bordey A. In Utero Electroporated Neurons for Medium-Throughput Screening of Compounds Regulating Neuron Morphology. ENeuro 2023, 10: eneuro.0160-23.2023. PMID: 37620147, PMCID: PMC10464655, DOI: 10.1523/eneuro.0160-23.2023.Peer-Reviewed Original ResearchConceptsSomatosensory cortexCortical pyramidal neuronsTreatment of epilepsyNeurite overgrowthNeurologic disabilityPyramidal neuronsSoma sizeNovel agentsCircuit alterationsSide effectsMorphologic assessmentMouse neuronsRelated disordersDiseased neuronsMTOR activatorDrug efficacyCandidate therapeuticsNeuronsNeuron morphologyMTOR activityMedium-throughput screeningNeurodevelopmental disordersNeurite lengthMorphologic measurementsDisorders
2019
GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations
Iffland PH, Carson V, Bordey A, Crino PB. GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia 2019, 60: 2163-2173. PMID: 31625153, PMCID: PMC7155771, DOI: 10.1111/epi.16370.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsEpilepsyGTPase-Activating ProteinsHumansMalformations of Cortical DevelopmentMutationTOR Serine-Threonine KinasesTumor Suppressor ProteinsConceptsCellular amino acid levelsRegulatory gene mutationsActivator RhebAmino acid levelsProtein complexesSingle geneRegulatory proteinsGene mutationsMechanistic targetNPRL3Rapamycin (mTOR) pathwayMTOR activationMTOR pathwayMutationsNPRL2MTOR inhibitionGenesFocal cortical dysplasia type IIaMTORDEPDC5ProteinPivotal rolePathwayRecent studiesNeuronal excitabilityHypervascularization in mTOR‐dependent focal and global cortical malformations displays differential rapamycin sensitivity
Zhang L, Huang T, Teaw S, Bordey A. Hypervascularization in mTOR‐dependent focal and global cortical malformations displays differential rapamycin sensitivity. Epilepsia 2019, 60: 1255-1265. PMID: 31125447, PMCID: PMC6558978, DOI: 10.1111/epi.15969.Peer-Reviewed Original ResearchConceptsBlood vesselsRapamycin treatmentVessel densityVessel abnormalitiesPostnatal day 14 miceAbsence of seizuresWild-type miceConditional transgenic miceTuberous sclerosis complexTypes of MCDDay 14 miceMCD modelFocal MCDMTOR blockersDysplastic neuronsFunctional outcomeEpilepsy treatmentSomatosensory cortexYoung miceFocal malformationsCortical developmentJuvenile miceTotal vessel lengthAnimal modelsTransgenic micemTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia
Nguyen LH, Mahadeo T, Bordey A. mTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia. Journal Of Neuroscience 2019, 39: 2762-2773. PMID: 30700531, PMCID: PMC6445990, DOI: 10.1523/jneurosci.2260-18.2019.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDisease Models, AnimalElectroencephalographyEpilepsyFemaleMaleMalformations of Cortical DevelopmentMiceSeverity of Illness IndexTOR Serine-Threonine KinasesTuberous SclerosisConceptsFocal cortical dysplasiaTuberous sclerosis complexSeverity of epilepsyRapamycin (mTOR) pathway genesPersonalized medicine strategiesAssociated neuropathologyCortical dysplasiaMouse modelActivity levelsPathogenic variantsEpileptogenic cortical malformationsNeuronal soma sizeMedicine strategiesPatient variantsMechanistic targetSevere epilepsy phenotypePreclinical drug testingHyperactivity levelsDose-dependent mannerMicroglial activationSeizure frequencyRecurrent seizuresCortical malformationsIntractable epilepsyClinical assessment
2016
Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration
Lin TV, Hsieh L, Kimura T, Malone TJ, Bordey A. Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 11330-11335. PMID: 27647922, PMCID: PMC5056085, DOI: 10.1073/pnas.1605740113.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCarrier ProteinsCell Cycle ProteinsDendritic SpinesEukaryotic Initiation FactorsExcitatory Postsynaptic PotentialsGene Knockdown TechniquesGreen Fluorescent ProteinsMatrix Attachment Region Binding ProteinsMechanistic Target of Rapamycin Complex 1MiceNeurogliaNeuronsPhosphoproteinsProtein BiosynthesisRas Homolog Enriched in Brain ProteinRNA CapsRNA, Small InterferingSignal TransductionTOR Serine-Threonine KinasesTranscription FactorsConceptsBrain cytoarchitectureUpper layer cortical neuronsHyperactive mammalian targetDendritic hypertrophyCortical neuronsCap-dependent translationEctopic placementRadial gliaMammalian targetLate corticogenesisTranslational repressor eukaryotic initiation factor 4EEukaryotic initiation factor 4ENeurodevelopmental disordersProtein 1Rapamycin complex 1Molecular hallmarksInitiation factor 4EMechanisms downstreamCytoarchitectureMolecular identityMisplacementActive mutantHypertrophyGliaOveractivationSwitching on mTORC1 induces neurogenesis but not proliferation in neural stem cells of young mice
Mahoney C, Feliciano DM, Bordey A, Hartman NW. Switching on mTORC1 induces neurogenesis but not proliferation in neural stem cells of young mice. Neuroscience Letters 2016, 614: 112-118. PMID: 26812181, DOI: 10.1016/j.neulet.2015.12.042.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell ProliferationMechanistic Target of Rapamycin Complex 1Mice, TransgenicMultiprotein ComplexesNeural Stem CellsNeurogenesisTamoxifenTOR Serine-Threonine KinasesConceptsNeural stem cellsSubventricular zoneNeonatal subventricular zoneWeek old miceTuberous sclerosis complexStem cellsNewborn neuroblastsYoung miceOld miceProgressive lossYoung adultsRapamycin complex 1Mechanistic targetRecent evidenceProliferative cellsMiceHyperactive mTORC1Terminal differentiationCellsMTORC1 activationProliferationActivationMTORC1NeurogenesisHyperactivity
2015
Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTOR in vivo
Gong X, Zhang L, Huang T, Lin TV, Miyares L, Wen J, Hsieh L, Bordey A. Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTOR in vivo. Human Molecular Genetics 2015, 24: 5746-5758. PMID: 26220974, PMCID: PMC4581604, DOI: 10.1093/hmg/ddv295.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsAxonsCarrier ProteinsCell Cycle ProteinsCell Growth ProcessesEukaryotic Initiation FactorsFemaleGene Expression RegulationGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaMaleMechanistic Target of Rapamycin Complex 1MiceMultiprotein ComplexesPhosphoproteinsRibosomal Protein S6 Kinases, 90-kDaSignal TransductionTOR Serine-Threonine KinasesConceptsAxon growthNew therapeutic optionsMultiple axon formationTherapeutic optionsHippocampal neuronsHyperactive mTORNeurological disordersUtero electroporationAxonal connectivityGSK3β activityTranslational repressor 4E-BPEukaryotic initiation factor 4EMTOR complex 1Translational targetsInitiation factor 4EHyperactive mTORC1VivoDownstream effectorsGSK3βAxon formationLong-range connectivityDominant negative mutantLithium chlorideMTORopathiesMTORC1
2014
MEK-ERK1/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR
Zhang L, Bartley CM, Gong X, Hsieh LS, Lin TV, Feliciano DM, Bordey A. MEK-ERK1/2-Dependent FLNA Overexpression Promotes Abnormal Dendritic Patterning in Tuberous Sclerosis Independent of mTOR. Neuron 2014, 84: 78-91. PMID: 25277454, PMCID: PMC4185153, DOI: 10.1016/j.neuron.2014.09.009.Peer-Reviewed Original ResearchConceptsDendritic complexityFLNA overexpressionDendritic abnormalitiesFLNA expressionDendritic patterningComplex dendritic arborsWild-type neuronsFilamin ADendritic arborsERK1/2-dependent mannerDendritic defectsNeurological defectsMEK-ERK1/2NeuronsMTOR activityNeurodevelopmental disordersNeurodevelopmental diseasesProtein filamin AAbnormalitiesMTOROverexpressionSelective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model
Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E, Minlebaev M, Goriounova NA, Buhler E, Watrin F, Shityakov S, Becker AJ, Bordey A, Milh M, Scavarda D, Bulteau C, Dorfmuller G, Delalande O, Represa A, Cardoso C, Dulac O, Ben-Ari Y, Burnashev N. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nature Communications 2014, 5: 4563. PMID: 25081057, PMCID: PMC4143949, DOI: 10.1038/ncomms5563.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnticonvulsantsDisease Models, AnimalElectroencephalographyEpilepsyGene Expression RegulationHeterozygoteHumansMaleMiceMice, TransgenicMicrotomyNeocortexPatch-Clamp TechniquesPyrazolesQuinolonesReceptors, N-Methyl-D-AspartateSignal TransductionTissue Culture TechniquesTOR Serine-Threonine KinasesTuberous SclerosisTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsConceptsN-methyl-D-aspartate receptorsTuberous sclerosis complexGluN2C expressionSpiny stellate cellsEarly postnatal lifeGluN2C/DPromising molecular targetBlock seizuresMTOR-dependent mannerSurgical resectionCortical tubersEarly epilepsyUnprovoked seizuresPharmacoresistant epilepsyTSC patientsSeizure generationBrain malformationsFunctional upregulationMurine modelStellate cellsPostnatal lifeRecurrent excitationTumor suppressor geneEpilepsySeizuresFMRP S499 Is Phosphorylated Independent of mTORC1-S6K1 Activity
Bartley CM, O’Keefe R, Bordey A. FMRP S499 Is Phosphorylated Independent of mTORC1-S6K1 Activity. PLOS ONE 2014, 9: e96956. PMID: 24806451, PMCID: PMC4013076, DOI: 10.1371/journal.pone.0096956.Peer-Reviewed Original ResearchEmbryonic Cerebrospinal Fluid Nanovesicles Carry Evolutionarily Conserved Molecules and Promote Neural Stem Cell Amplification
Feliciano DM, Zhang S, Nasrallah CM, Lisgo SN, Bordey A. Embryonic Cerebrospinal Fluid Nanovesicles Carry Evolutionarily Conserved Molecules and Promote Neural Stem Cell Amplification. PLOS ONE 2014, 9: e88810. PMID: 24533152, PMCID: PMC3923048, DOI: 10.1371/journal.pone.0088810.Peer-Reviewed Original ResearchConceptsNeural stem cellsRapamycin complex 1 (mTORC1) pathwayIntracellular pathwaysStem cell amplificationInsulin-like growth factorCoordinated regulationGenetic programMicroRNA componentsExosome NanovesiclesEmbryonic CSFCell amplificationStem cellsENSCsPathwayCoordinated transferGrowth factorHuman embryosBrain developmentNanovesiclesMixed cultureAmplificationMoleculesEmbryosProteinExosomes
2013
mTORC1 Targets the Translational Repressor 4E-BP2, but Not S6 Kinase 1/2, to Regulate Neural Stem Cell Self-Renewal In Vivo
Hartman NW, Lin TV, Zhang L, Paquelet GE, Feliciano DM, Bordey A. mTORC1 Targets the Translational Repressor 4E-BP2, but Not S6 Kinase 1/2, to Regulate Neural Stem Cell Self-Renewal In Vivo. Cell Reports 2013, 5: 433-444. PMID: 24139800, DOI: 10.1016/j.celrep.2013.09.017.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCarrier ProteinsCell Cycle ProteinsCell DifferentiationCells, CulturedEukaryotic Initiation FactorsMechanistic Target of Rapamycin Complex 1MiceMonomeric GTP-Binding ProteinsMultiprotein ComplexesNeural Stem CellsNeuropeptidesPhosphoproteinsPhosphorylationRas Homolog Enriched in Brain ProteinRibosomal Protein S6 Kinases, 90-kDaRNA InterferenceRNA, Small InterferingSirolimusTOR Serine-Threonine KinasesConceptsCap-dependent translationNeural stem cellsNSC differentiationStem Cell Self-RenewalTranslational repressor 4E-BP1P70 S6 kinase 1Neural Stem Cell Self-RenewalCell Self-RenewalRapamycin complex 1Neonatal neural stem cellsS6 kinase 1Downstream regulatory mechanismsLineage expansionSelf-RenewalRegulatory mechanismsKinase 1Kinase 1/2Constitutive activationMammalian targetCell growthStem cellsBrain sizeDifferentiationKnockdownNeuron productionA circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits
Feliciano DM, Lin TV, Hartman NW, Bartley CM, Kubera C, Hsieh L, Lafourcade C, O'Keefe RA, Bordey A. A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits. International Journal Of Developmental Neuroscience 2013, 31: 667-678. PMID: 23485365, PMCID: PMC3830611, DOI: 10.1016/j.ijdevneu.2013.02.008.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsCentral Nervous SystemCognition DisordersDisease Models, AnimalEpilepsyHumansMiceTOR Serine-Threonine KinasesTuberous SclerosisConceptsTuberous sclerosis complexCortical lesionsBrain lesionsLoss of heterozygosityNeuronal functionNovel therapeutic targetNeuronal circuit formationMolecular mechanisms downstreamRecent mouse modelsNeurological manifestationsNeurological presentationTSC patientsBenign tumorsBrain malformationsDiscrete lesionsMouse modelNeuropsychiatric problemsTherapeutic targetSynaptic plasticityPerinatal developmentCircuit formationLesionsMTOR hyperactivityNeurocognitive deficitsPsychological impairmentRheb Activation in Subventricular Zone Progenitors Leads to Heterotopia, Ectopic Neuronal Differentiation, and Rapamycin-Sensitive Olfactory Micronodules and Dendrite Hypertrophy of Newborn Neurons
Lafourcade CA, Lin TV, Feliciano DM, Zhang L, Hsieh LS, Bordey A. Rheb Activation in Subventricular Zone Progenitors Leads to Heterotopia, Ectopic Neuronal Differentiation, and Rapamycin-Sensitive Olfactory Micronodules and Dendrite Hypertrophy of Newborn Neurons. Journal Of Neuroscience 2013, 33: 2419-2431. PMID: 23392671, PMCID: PMC3711634, DOI: 10.1523/jneurosci.1840-12.2013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornCell DifferentiationCell EnlargementCell Line, TumorCell MovementCerebral VentriclesDendritesElectroporationFemaleHypertrophyMaleMiceMonomeric GTP-Binding ProteinsNeural Stem CellsNeurogenesisNeuronsNeuropeptidesOlfactory BulbRas Homolog Enriched in Brain ProteinSirolimusStem CellsTOR Serine-Threonine KinasesConceptsNeural progenitor cellsWild-type miceOlfactory bulbMTOR activitySynaptic inputsEctopic neuronal differentiationSubventricular zone neural progenitor cellsActive ras homologNeuronal differentiationGABAergic synaptic inputsTsc1 mutant miceSubventricular zone progenitorsDendritic complexityNewborn neuronsTuberous sclerosisOlig2 cellsHyperactive mTORHeterozygote miceCircuit formationAction potentialsNeuronal morphologyNewborn cellsMutant miceEctopic cellsMammalian target
2011
Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion
Feliciano DM, Quon JL, Su T, Taylor MM, Bordey A. Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion. Human Molecular Genetics 2011, 21: 799-810. PMID: 22068588, PMCID: PMC3263992, DOI: 10.1093/hmg/ddr511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornCell MovementCerebral CortexDendritesElectroporationFemaleGene DeletionMaleMiceMice, TransgenicNeurogenesisNeurogliaNeuronsOlfactory BulbPeriventricular Nodular HeterotopiaSingle-Cell AnalysisTOR Serine-Threonine KinasesTuberous SclerosisTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsConceptsTuberous sclerosis complexSubventricular zoneBrain lesionsPostnatal subventricular zoneForebrain structuresTsc1 deletionHuman subventricular zoneCortical infiltrationNeurological symptomsNeuropsychiatric symptomsNon-invasive imagingOlfactory lesionsPostnatal neurogenesisTSC patientsPersistent infiltrationTransgenic miceAbnormal circuitsStructural abnormalitiesDendritic treeNeuronal precursorsLesionsEmbryonic neurogenesisNeurogenesisNeuronsMicronodulesSingle-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice
Feliciano DM, Su T, Lopez J, Platel JC, Bordey A. Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. Journal Of Clinical Investigation 2011, 121: 1596-1607. PMID: 21403402, PMCID: PMC3069783, DOI: 10.1172/jci44909.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesBase SequenceCell SizeCerebral CortexDisease Models, AnimalDNA PrimersFemaleGene Knockout TechniquesMiceMice, 129 StrainMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, Mutant StrainsMice, TransgenicPregnancySeizuresTOR Serine-Threonine KinasesTuberous SclerosisTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsConceptsTuberous sclerosis complexSeizure thresholdNeuronal populationsSigns of gliosisLower seizure thresholdContribution of astrocytesDiscrete neuronal populationsAutosomal dominant disorderHeterotopic nodulesCortical hyperexcitabilityCortical tubersCortical lesionsGlial reactivityIntractable seizuresCortical malformationsSoma sizeAnimal modelsTSC1 gene productAffected neuronsDendritic treeGiant cellsUtero electroporationMutant miceLesion formationMammalian target