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 effectorsMiceFilamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations
Zhang L, Huang T, Teaw S, Nguyen LH, Hsieh LS, Gong X, Burns LH, Bordey A. Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations. Science Translational Medicine 2020, 12 PMID: 32075941, DOI: 10.1126/scitranslmed.aay0289.Peer-Reviewed Original ResearchConceptsFocal cortical dysplasia type IITuberous sclerosis complexFocal cortical malformationsCortical malformationsSeizure frequencyReduced seizure frequencyVehicle-treated miceOnset of seizuresFilamin ALifelong epilepsyShort hairpin RNANeurological comorbiditiesNeuronal abnormalitiesSeizure activityEpilepsy treatmentSeizure onsetMouse modelAdult miceFLNA expressionPatientsCortical tissueMiceSeizuresMalformationsHairpin RNAConvulsive 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
2024
The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function
Nguyen L, Xu Y, Nair M, Bordey A. The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. ELife 2024, 12: rp91010. PMID: 38411613, PMCID: PMC10942629, DOI: 10.7554/elife.91010.Peer-Reviewed Original ResearchConceptsMouse medial prefrontal cortexMedial prefrontal cortexFocal malformations of cortical developmentMalformations of cortical developmentExcitatory synaptic activityExcitatory synaptic transmissionCortical neuron developmentPyramidal neuron morphologyMechanisms of hyperexcitabilityResponse to therapeutic interventionsMTORC1 signalingGene-specific mechanismsPrefrontal cortexFocal malformationsBrain somatic mutationsMTOR complex 1Membrane excitabilityBiallelic inactivationClinical manifestationsGene mutationsNetwork hyperexcitabilitySynaptic transmissionSynaptic activityIntractable epilepsyRepressor gene
2023
Semi-natural housing rescues social behavior and reduces repetitive exploratory behavior of BTBR autistic-like mice
Binder M, Bordey A. Semi-natural housing rescues social behavior and reduces repetitive exploratory behavior of BTBR autistic-like mice. Scientific Reports 2023, 13: 16260. PMID: 37758896, PMCID: PMC10533821, DOI: 10.1038/s41598-023-43558-0.Peer-Reviewed Original ResearchIn 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 measurementsDisordersThe Novel Somatosensory Nose-Poke Adapted Paradigm (SNAP) Is an Effective Tool to Assess Differences in Tactile Sensory Preferences in Autistic-Like Mice
Binder M, Bordey A. The Novel Somatosensory Nose-Poke Adapted Paradigm (SNAP) Is an Effective Tool to Assess Differences in Tactile Sensory Preferences in Autistic-Like Mice. ENeuro 2023, 10: eneuro.0478-22.2023. PMID: 37596047, PMCID: PMC10470849, DOI: 10.1523/eneuro.0478-22.2023.Peer-Reviewed Original Research
2022
Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex
Nguyen LH, Leiser SC, Song D, Brunner D, Roberds SL, Wong M, Bordey A. Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex. Epilepsy Research 2022, 181: 106890. PMID: 35219048, PMCID: PMC8930622, DOI: 10.1016/j.eplepsyres.2022.106890.Peer-Reviewed Original ResearchConceptsTuberous sclerosis complexMouse modelTSC mouse modelsDevelopmental brain malformationsMEK-ERKNovel treatment targetsMEK inhibitor PD0325901Intractable epilepsySeizure activityTSC patientsSeizure suppressionBrain malformationsMTOR inhibitorsTreatment targetsMEK-ERK activitySeizuresTSC neuropathologyPotential alternative strategyMEK-ERK inhibitionInhibitor PD0325901Monogenic disordersInhibitionMTORTreatmentEverolimus
2021
Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2
Spinelli M, Boucard C, Ornaghi S, Schoeberlein A, Irene K, Coman D, Hyder F, Zhang L, Haesler V, Bordey A, Barnea E, Paidas M, Surbek D, Mueller M. Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2. JCI Insight 2021, 6: e132335. PMID: 34676826, PMCID: PMC8564895, DOI: 10.1172/jci.insight.132335.Peer-Reviewed Original ResearchConceptsSynthetic preimplantation factorNuclear receptor corepressor 2PreImplantation FactorHypoxic-ischemic brain injuryDiffuse white matter injuryWhite matter injuryS-adenosylhomocysteine hydrolaseOligodendrocyte differentiation markersMyelin preservationPremature birthBrain recoveryBrain injuryMyelin protectionRNA H19Neurodegenerative diseasesOligodendrocyte fateDifferentiation markersInjuryH19Cellular componentsDiverse cellular componentsOligodendrocytesGliogenesisDiseaseNeurotransmittersSmall Extracellular Vesicles Control Dendritic Spine Development through Regulation of HDAC2 Signaling
Zhang L, Lin TV, Yuan Q, Sadoul R, Lam TT, Bordey A. Small Extracellular Vesicles Control Dendritic Spine Development through Regulation of HDAC2 Signaling. Journal Of Neuroscience 2021, 41: 3799-3807. PMID: 33741723, PMCID: PMC8084316, DOI: 10.1523/jneurosci.0766-20.2021.Peer-Reviewed Original ResearchConceptsSmall extracellular vesiclesRegulation of HDAC2Extracellular vesiclesSpine developmentCell-cell signalingTranscriptional programsCortical neuronsSEV releaseTranscriptional decreaseDendritic spinesNeuronal developmentNeuron developmentDendritic spine developmentLines of evidenceHDAC2Paracrine communicationAge-dependent decreaseVesiclesPopulations of neuronsRegulationLC-MS/MSHDAC2 levelsSynaptic targetsExcitatory synapsesSpine growthRab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex
Zhang L, Zhang X, Hsieh LS, Lin TV, Bordey A. Rab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex. Cells 2021, 10: 622. PMID: 33799820, PMCID: PMC8000154, DOI: 10.3390/cells10030622.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedDendritic SpinesExcitatory Postsynaptic PotentialsExtracellular VesiclesFemaleGene Expression Regulation, DevelopmentalGestational AgeMiceParacrine CommunicationPregnancyPyramidal CellsRab27 GTP-Binding ProteinsSensory Receptor CellsSomatosensory CortexSynaptic TransmissionVibrissaeConceptsSmall extracellular vesiclesL4 neuronsParacrine communicationExcitatory synaptic transmissionRelease of sEVsDendritic spine formationCell-autonomous effectsRisk of autismL2/3 neuronsPyramidal neuronsLayer 2/3Somatosensory cortexBarrel cortexCortical neuronsSynaptic transmissionWhisker stimulationSomatosensory informationJuvenile miceSynaptic connectivitySynaptic integrationSpine formationBrain developmentNeuronsSensory stimulationSpine development
2019
Hypervascularization 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 ResearchConceptsFocal 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
2018
In utero electroporation-based translating ribosome affinity purification identifies age-dependent mRNA expression in cortical pyramidal neurons
Huang T, Nguyen L, Lin TV, Gong X, Zhang L, Kim GB, Sarkisian MR, Breunig JJ, Bordey A. In utero electroporation-based translating ribosome affinity purification identifies age-dependent mRNA expression in cortical pyramidal neurons. Neuroscience Research 2018, 143: 44-52. PMID: 29857015, PMCID: PMC6265126, DOI: 10.1016/j.neures.2018.05.006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainDisks Large Homolog 4 ProteinDoublecortin ProteinElectroporationEmbryonic DevelopmentFemaleGene Expression ProfilingGene Expression Regulation, DevelopmentalGreen Fluorescent ProteinsMaleMiceOligonucleotide Array Sequence AnalysisProtein BiosynthesisPyramidal CellsRecombinant Fusion ProteinsRibosomal Protein L10Ribosomal ProteinsRNA, MessengerSomatosensory CortexSynapsinsConceptsSpecific neuronal populationsRibosomal protein L10aRibosome affinity purificationSelective biological processesNeuronal genesMolecular profileSpecific developmental patternsTarget genesAffinity purificationBiological processesGenesUtero electroporationNeuronal populationsEmbryonic day 14Molecular profilingDevelopmental patternsMRNA expression
2017
Valnoctamide Inhibits Cytomegalovirus Infection in Developing Brain and Attenuates Neurobehavioral Dysfunctions and Brain Abnormalities
Ornaghi S, Hsieh LS, Bordey A, Vergani P, Paidas MJ, van den Pol AN. Valnoctamide Inhibits Cytomegalovirus Infection in Developing Brain and Attenuates Neurobehavioral Dysfunctions and Brain Abnormalities. Journal Of Neuroscience 2017, 37: 6877-6893. PMID: 28630251, PMCID: PMC5518418, DOI: 10.1523/jneurosci.0970-17.2017.Peer-Reviewed Original ResearchConceptsAnti-CMV drugsBrain defectsNeurological outcomeCMV replicationMouse brainAvailable anti-CMV drugsHuman fetal brain cellsLong-term neurological outcomeTreatment of cytomegalovirusAdverse neurological outcomesUninfected control miceCommon infectious causeLong-term motorSecond trimester human fetusesUninfected control animalsFetal brain cellsHuman fetal astrocytesJuvenile male miceWeeks of lifeAdverse side effectsEfficacious therapeutic effectsDetectable adverse effectsNewborn mouse brainLevels of virusCMV infection
2016
Mammalian FMRP S499 Is Phosphorylated by CK2 and Promotes Secondary Phosphorylation of FMRP
Bartley CM, O’Keefe R, Blice-Baum A, Mihailescu MR, Gong X, Miyares L, Karaca E, Bordey A. Mammalian FMRP S499 Is Phosphorylated by CK2 and Promotes Secondary Phosphorylation of FMRP. ENeuro 2016, 3: eneuro.0092-16.2016. PMID: 27957526, PMCID: PMC5116651, DOI: 10.1523/eneuro.0092-16.2016.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCasein Kinase IICells, CulturedCerebral CortexFragile X Mental Retardation ProteinHEK293 CellsHumansMass SpectrometryMiceNaphthyridinesPhenazinesPhosphorylationProtein BiosynthesisProtein Kinase InhibitorsReceptors, Metabotropic GlutamateRecombinant ProteinsTime FactorsConceptsTranslational repressionNearby residuesProtein phosphatase 2ACasein kinase IIMental retardation proteinFMRP lossPhosphatase 2AFragile X syndromePP2A pathwaySecondary phosphorylationProtein translationKinase IIGene transcriptsFMRPBrain transcriptsFunction mutationsPhosphorylationS499X syndromeTranscriptsRepressionResiduesRecent evidenceCK2KinaseNormalizing 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 mutantHypertrophyGliaOveractivationTsc1 haploinsufficiency is sufficient to increase dendritic patterning and Filamin A levels
Zhang L, Huang T, Bordey A. Tsc1 haploinsufficiency is sufficient to increase dendritic patterning and Filamin A levels. Neuroscience Letters 2016, 629: 15-18. PMID: 27345385, PMCID: PMC4983256, DOI: 10.1016/j.neulet.2016.06.037.Peer-Reviewed Original ResearchConceptsTuberous sclerosis complexDendritic complexityDendritic patterningTotal dendritic lengthTsc1 haploinsufficiencyFLNA levelsNeonatal electroporationDendritic lengthNewborn neuronsDendritic abnormalitiesSholl analysisOlfactory bulbFilamin ATsc1 lossHeterozygote miceCognitive defectsDendritic morphologyMiceA levelsMost individualsHaploinsufficiencyHeterozygote conditionLevelsAbnormalitiesNeurons
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 chlorideMTORopathiesMTORC1PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling
Mueller M, Schoeberlein A, Zhou J, Joerger-Messerli M, Oppliger B, Reinhart U, Bordey A, Surbek D, Barnea ER, Huang Y, Paidas M. PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling. Cell Death & Differentiation 2015, 22: 2078-2086. PMID: 25976303, PMCID: PMC4816111, DOI: 10.1038/cdd.2015.55.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBcl-Associated Death ProteinBrain InjuriesCell Line, TumorCell SurvivalCyclic AMPCyclic AMP Response Element-Binding ProteinCyclic AMP-Dependent Protein KinasesDisease Models, AnimalGAP-43 ProteinMiceMicroRNAsNeuroprotective AgentsPeptidesProtein Kinase CProto-Oncogene Proteins c-bcl-2RatsRNA InterferenceSignal TransductionToll-Like Receptor 4ConceptsPreImplantation FactorCentral nervous system damageExperimental autoimmune encephalomyelitisPerinatal brain injuryBrain injury modelNervous system damageExpression of GAP43Autoimmune encephalomyelitisTLR4 expressionNeuronal lossPotential clinical applicationsCNS diseaseNeuronal deathBrain injuryClinical trialsInjury modelFast-track approvalProtective effectRodent modelsGAP-43NeuroprotectionSystem damageNeuronal growthProtein kinaseCortical architecture