Featured Publications
Neuronal impact of patient-specific aberrant NRXN1α splicing
Flaherty E, Zhu S, Barretto N, Cheng E, Deans PJM, Fernando MB, Schrode N, Francoeur N, Antoine A, Alganem K, Halpern M, Deikus G, Shah H, Fitzgerald M, Ladran I, Gochman P, Rapoport J, Tsankova NM, McCullumsmith R, Hoffman GE, Sebra R, Fang G, Brennand KJ. Neuronal impact of patient-specific aberrant NRXN1α splicing. Nature Genetics 2019, 51: 1679-1690. PMID: 31784728, PMCID: PMC7451045, DOI: 10.1038/s41588-019-0539-z.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsAutism Spectrum DisorderBipolar DisorderCalcium-Binding ProteinsCase-Control StudiesDepressive Disorder, MajorFemaleGene ExpressionHeterozygoteHumansInduced Pluripotent Stem CellsMaleMiceNeural Cell Adhesion MoleculesProtein IsoformsSchizophreniaSequence Deletion
2023
Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder
Mishra H, Wei H, Rohr K, Ko I, Nievergelt C, Maihofer A, Shilling P, Alda M, Berrettini W, Brennand K, Calabrese J, Coryell W, Frye M, Gage F, Gershon E, McInnis M, Nurnberger J, Oedegaard K, Zandi P, Kelsoe J, McCarthy M. Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder. European Neuropsychopharmacology 2023, 74: 1-14. PMID: 37126998, DOI: 10.1016/j.euroneuro.2023.04.009.Peer-Reviewed Original ResearchConceptsCell survival genesCircadian clockSurvival genesCell survivalCircadian clock genesCircadian rhythmGenetic variationClock genesKnockdown studiesCaspase activityCell deathMolecular pathwaysPrimary fibroblastsCellular modelGenesMouse fibroblastsFibroblast modelApoptosisStaurosporinePER1FibroblastsOpposite mannerLithium responsivenessDistinct patternsClock
2022
Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
Fulton S, Wenderski W, Lepack A, Eagle A, Fanutza T, Bastle R, Ramakrishnan A, Hays E, Neal A, Bendl J, Farrelly L, Al-Kachak A, Lyu Y, Cetin B, Chan J, Tran T, Neve R, Roper R, Brennand K, Roussos P, Schimenti J, Friedman A, Shen L, Blitzer R, Robison A, Crabtree G, Maze I. Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome. Nature Communications 2022, 13: 6384. PMID: 36289231, PMCID: PMC9606253, DOI: 10.1038/s41467-022-34200-0.Peer-Reviewed Original ResearchConceptsGene expressionChromatin accessibilityChromatin effectorsBAF chromatinGenetic basisTrisomic animalsIPS cellsBRWD1Chromosome 21Down syndromeHSA21Ts65Dn mouse modelCommon chromosomal conditionExpressionChromatinNormal neurodevelopmentChromosomal conditionHippocampal LTPMouse modelMistargetingGenesTrisomic miceCognitive deficitsEffectorsSyndromeA bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning
Hafez A, Zimmerman A, Papageorgiou G, Chandrasekaran J, Amoah S, Lin R, Lozano E, Pierotti C, Dell'Orco M, Hartley B, Alural B, Lalonde J, Esposito J, Berretta S, Squassina A, Chillotti C, Voloudakis G, Shao Z, Fullard J, Brennand K, Turecki G, Roussos P, Perlis R, Haggarty S, Perrone-Bizzozero N, Brigman J, Mellios N. A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning. Cell Reports 2022, 38: 110282. PMID: 35045295, PMCID: PMC8809079, DOI: 10.1016/j.celrep.2021.110282.Peer-Reviewed Original ResearchConceptsImportance of circRNAsRNA-binding proteinSynaptic gene expressionCircular RNAsGene expressionOrbitofrontal cortexCompetitive interactionsComplete rescuePsychiatric disordersKnockdownSynaptic expressionMechanistic insightsBrain functionMRNAHomer1bBehavioral flexibilityNeuronal culturesExpressionBiogenesisCircRNAsRNAProteinRegulatesReversal learningDisorders
2021
Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets
Neff R, Wang M, Vatansever S, Guo L, Ming C, Wang Q, Wang E, Horgusluoglu-Moloch E, Song W, Li A, Castranio E, Julia T, Ho L, Goate A, Fossati V, Noggle S, Gandy S, Ehrlich M, Katsel P, Schadt E, Cai D, Brennand K, Haroutunian V, Zhang B. Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets. Science Advances 2021, 7: eabb5398. PMID: 33523961, PMCID: PMC7787497, DOI: 10.1126/sciadv.abb5398.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseMouse modelAD mouse modelDiverse pathophysiologic mechanismsTau-mediated neurodegenerationMajor molecular subtypesSpecific mouse modelsPathophysiologic mechanismsHuman trialsMolecular subtypesImmune activityHeterogeneous diseaseAD cohortAD subtypesBrain regionsSynaptic signalingMolecular subtypingSubtype heterogeneityDiseaseCommon formPrecision medicineMultiscale network analysisDevastating diseaseMolecular heterogeneitySubtypes
2020
Cell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models
Gregory JA, Hoelzli E, Abdelaal R, Braine C, Cuevas M, Halpern M, Barretto N, Schrode N, Akbalik G, Kang K, Cheng E, Bowles K, Lotz S, Goderie S, Karch CM, Temple S, Goate A, Brennand KJ, Phatnani H. Cell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models. Cells 2020, 9: 1406. PMID: 32516938, PMCID: PMC7349756, DOI: 10.3390/cells9061406.Peer-Reviewed Original ResearchConceptsCell type-restricted expressionDisease-associated interactionsGene expression profilingHiPSC-derived motor neuronsHuman-induced pluripotent stem cellsPluripotent stem cellsCell-type specific perturbationsImmortalized cell linesRibosomal proteinsGenomic studiesExpression profilingMolecular mechanismsOff-target RNAMouse tissuesCell typesStem cellsPrimary mouse astrocytesExperimental replicatesCell linesMixed speciesMouse astrocytesExpressionMotor neuronsRiboTagCellsSex-Specific Role for the Long Non-coding RNA LINC00473 in Depression
Issler O, van der Zee YY, Ramakrishnan A, Wang J, Tan C, Loh YE, Purushothaman I, Walker DM, Lorsch ZS, Hamilton PJ, Peña CJ, Flaherty E, Hartley BJ, Torres-Berrío A, Parise EM, Kronman H, Duffy JE, Estill MS, Calipari ES, Labonté B, Neve RL, Tamminga CA, Brennand KJ, Dong Y, Shen L, Nestler EJ. Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression. Neuron 2020, 106: 912-926.e5. PMID: 32304628, PMCID: PMC7305959, DOI: 10.1016/j.neuron.2020.03.023.Peer-Reviewed Original ResearchConceptsSex-specific phenotypesLong non-coding RNAsNon-coding RNAsStress resilienceHuman neuron-like cellsRegulatory transcriptsSex-specific patternsSex-specific roleNeuron-like cellsGene expressionFemale miceLong NonViral-mediated gene transferGene transferLINC00473Prefrontal cortexSynaptic functionRate of menPhenotypeCommon disorderPFC neuronsDepressed femalesDepressed humansFemale depressionComplex regionA psychiatric disease-related circular RNA controls synaptic gene expression and cognition
Zimmerman AJ, Hafez AK, Amoah SK, Rodriguez BA, Dell’Orco M, Lozano E, Hartley BJ, Alural B, Lalonde J, Chander P, Webster MJ, Perlis RH, Brennand KJ, Haggarty SJ, Weick J, Perrone-Bizzozero N, Brigman JL, Mellios N. A psychiatric disease-related circular RNA controls synaptic gene expression and cognition. Molecular Psychiatry 2020, 25: 2712-2727. PMID: 31988434, PMCID: PMC7577899, DOI: 10.1038/s41380-020-0653-4.Peer-Reviewed Original ResearchConceptsSynaptic gene expressionCircular RNAsGene expressionAlternative mRNA transcriptsDisease-associated circRNAsHomolog 1Neuronal RNAMRNA transcriptsRNASynaptic expressionAge of onsetMammalian brainCircRNAsPotential involvementDorsolateral prefrontal cortexOrbitofrontal cortexBipolar disorderPrefrontal cortexKnockdownExpressionFrontal cortexSynaptic plasticityNeuronal culturesPsychiatric diseasesMouse orbitofrontal cortex
2018
GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis
Kajiwara Y, Wang E, Wang M, Sin WC, Brennand KJ, Schadt E, Naus CC, Buxbaum J, Zhang B. GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis. Acta Neuropathologica Communications 2018, 6: 144. PMID: 30577786, PMCID: PMC6303945, DOI: 10.1186/s40478-018-0642-x.Peer-Reviewed Original ResearchConceptsPost-mortem Alzheimer's diseaseAlzheimer's diseaseTop key driverRNA sequencing analysisDisease pathogenesisProteomic datasetsKey regulatorNormal control brainsGJA1 expressionAlzheimer's disease (AD) pathogenesisApoE protein levelsPromising pharmacological targetSequencing analysisGJA1Wildtype astrocytesWildtype neuronsAβ metabolismAβ phagocytosisProtein levelsControl brainsAD pathogenesisAD amyloidPharmacological targetsAstrocytesCognitive functionChronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder
McCarthy MJ, Wei H, Nievergelt CM, Stautland A, Maihofer AX, Welsh DK, Shilling P, Alda M, Alliey-Rodriguez N, Anand A, Andreasson OA, Balaraman Y, Berrettini WH, Bertram H, Brennand KJ, Calabrese JR, Calkin CV, Claasen A, Conroy C, Coryell WH, Craig DW, D’Arcangelo N, Demodena A, Djurovic S, Feeder S, Fisher C, Frazier N, Frye MA, Gage FH, Gao K, Garnham J, Gershon ES, Glazer K, Goes F, Goto T, Harrington G, Jakobsen P, Kamali M, Karberg E, Kelly M, Leckband SG, Lohoff F, McInnis MG, Mondimore F, Morken G, Nurnberger JI, Obral S, Oedegaard KJ, Ortiz A, Ritchey M, Ryan K, Schinagle M, Schoeyen H, Schwebel C, Shaw M, Shekhtman T, Slaney C, Stapp E, Szelinger S, Tarwater B, Zandi PP, Kelsoe JR. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacology 2018, 44: 620-628. PMID: 30487653, PMCID: PMC6333516, DOI: 10.1038/s41386-018-0273-8.Peer-Reviewed Original ResearchConceptsBipolar disorderEffects of lithiumMaintenance treatmentBD patientsCircadian rhythmMinority of patientsLithium maintenance treatmentMood stabilizer treatmentSerious mood disorderCircadian rhythm abnormalitiesCircadian rhythm parametersClinical responseCircadian rhythm functionLithium monotherapyClinical trialsMood disordersRhythm abnormalitiesMood symptomsPharmacological effectsPatientsEvening chronotypeStabilizer treatmentCommon genetic variationRhythm parametersMonotherapy
2017
The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain
Jiang Y, Loh YE, Rajarajan P, Hirayama T, Liao W, Kassim BS, Javidfar B, Hartley BJ, Kleofas L, Park RB, Labonte B, Ho SM, Chandrasekaran S, Do C, Ramirez BR, Peter CJ, C W JT, Safaie BM, Morishita H, Roussos P, Nestler EJ, Schaefer A, Tycko B, Brennand KJ, Yagi T, Shen L, Akbarian S. The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nature Genetics 2017, 49: 1239-1250. PMID: 28671686, PMCID: PMC5560095, DOI: 10.1038/ng.3906.Peer-Reviewed Original ResearchVariations in brain defects result from cellular mosaicism in the activation of heat shock signalling
Ishii S, Torii M, Son AI, Rajendraprasad M, Morozov YM, Kawasawa YI, Salzberg AC, Fujimoto M, Brennand K, Nakai A, Mezger V, Gage FH, Rakic P, Hashimoto-Torii K. Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling. Nature Communications 2017, 8: 15157. PMID: 28462912, PMCID: PMC5418582, DOI: 10.1038/ncomms15157.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsBrainCell MovementEmbryo, MammalianEthanolFemaleGene Expression Regulation, DevelopmentalHeat Shock Transcription FactorsHumansHydrogen PeroxideInjections, IntraperitonealMaleMaternal ExposureMiceMice, TransgenicNeural Stem CellsNeuronsPhenotypePregnancyPrenatal Exposure Delayed EffectsPrimary Cell CultureSignal TransductionMEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice
Mitchell A, Javidfar B, Pothula V, Ibi D, Shen E, Peter C, Bicks L, Fehr T, Jiang Y, Brennand K, Neve R, Gonzalez-Maeso J, Akbarian S. MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Molecular Psychiatry 2017, 23: 123-132. PMID: 28115742, PMCID: PMC5966823, DOI: 10.1038/mp.2016.254.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainChromatin ImmunoprecipitationCognition DisordersComputational BiologyDisease Models, AnimalEpigenomicsGene Expression RegulationGreen Fluorescent ProteinsHistonesMEF2 Transcription FactorsMiceMice, Inbred C57BLMice, KnockoutNerve Tissue ProteinsNeuronsPolymorphism, Single NucleotideSchizophreniaTransduction, GeneticConceptsTherapeutic potentialPrefrontal projection neuronsNeuron-specific promoterUnexplored therapeutic potentialProjection neuronsDrug challengeDisease casesRelated disordersRisk architecturePrefrontal cortexSchizophreniaSingle nucleotide polymorphismsCognitive performancePsychiatric Genomics ConsortiumNeuronal genomeH3K4 hypermethylationRisk lociCognitive enhancement
2016
Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models
Xu J, Hartley BJ, Kurup P, Phillips A, Topol A, Xu M, Ononenyi C, Foscue E, Ho SM, Baguley TD, Carty N, Barros CS, Müller U, Gupta S, Gochman P, Rapoport J, Ellman JA, Pittenger C, Aronow B, Nairn AC, Nestor MW, Lombroso PJ, Brennand KJ. Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular Psychiatry 2016, 23: 271-281. PMID: 27752082, PMCID: PMC5395367, DOI: 10.1038/mp.2016.163.Peer-Reviewed Original ResearchConceptsBrain-specific tyrosine phosphataseDephosphorylation of GluN2BExtracellular signal-regulated kinase 1/2Signal-regulated kinase 1/2Glutamate receptor internalizationPluripotent stem cellsKnockout mouse modelTyrosine phosphataseMouse modelKinase 1/2Receptor internalizationImportant regulatorGenetic reductionLoss of NMDARsStem cellsN-methyl DPharmacological inhibitionProtein levelsSynaptic functionSTEP61Patient cohortForebrain neuronsBehavioral deficitsExcitatory neuronsSchizophrenia model
2014
Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders
Hashimoto-Torii K, Torii M, Fujimoto M, Nakai A, Fatimy R, Mezger V, Ju MJ, Ishii S, Chao SH, Brennand KJ, Gage FH, Rakic P. Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders. Neuron 2014, 82: 560-572. PMID: 24726381, PMCID: PMC4051437, DOI: 10.1016/j.neuron.2014.03.002.Peer-Reviewed Original ResearchConceptsCerebral cortical cellsHuman neural progenitor cellsNeural progenitor cellsHeat shock factor 1Maternal seizuresSeizure susceptibilityPrenatal exposureNeuropsychiatric dysfunctionShock factor 1Neuronal responsesBrain cellsSchizophrenia patientsBrain disordersLate onsetMouse cortexStructural abnormalitiesNeuropsychiatric disordersHSF1 deficiencyExposure of embryosProgenitor cellsSubthreshold levelsFactor 1Induced pluripotent stem cellsEnvironmental insultsCortical cellsPhenotypic differences in hiPSC NPCs derived from patients with schizophrenia
Brennand K, Savas J, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont K, Kim H, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao S, Mrksich M, Rakic P, Fang G, Zhang B, Yates J, Gage F. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular Psychiatry 2014, 20: 361-368. PMID: 24686136, PMCID: PMC4182344, DOI: 10.1038/mp.2014.22.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAntipsychotic AgentsCell DifferentiationCell MovementCells, CulturedFemaleGene ExpressionHumansMaleMiceMice, Inbred C57BLMice, TransgenicMitochondriaNeural Cell Adhesion MoleculesNeural Stem CellsOxidative StressPhenotypePluripotent Stem CellsProsencephalonProteomicsReactive Oxygen SpeciesSchizophreniaYoung AdultConceptsHiPSC neural progenitor cellsNeural progenitor cellsHuman-induced pluripotent stem cellsHiPSC-derived neuronsGene expressionGene expression comparisonsStable isotope labelingProteomic mass spectrometry analysisAbnormal gene expressionPluripotent stem cellsOxidative stressCytoskeletal remodelingMass spectrometry analysisCellular phenotypesExpression comparisonsDevelopmental mechanismsIsotope labelingPhenotypic differencesBrainSpan AtlasDisease predispositionAmino acidsScalable assayNPC phenotypeStem cellsProgenitor cells
2012
Modeling Schizophrenia Using Induced Pluripotent Stem Cell–Derived and Fibroblast-Induced Neurons
Tran N, Ladran I, Brennand K. Modeling Schizophrenia Using Induced Pluripotent Stem Cell–Derived and Fibroblast-Induced Neurons. Schizophrenia Bulletin 2012, 39: 4-10. PMID: 23172000, PMCID: PMC3523925, DOI: 10.1093/schbul/sbs127.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
2011
Concise Review: The Promise of Human Induced Pluripotent Stem Cell‐Based Studies of Schizophrenia
Brennand K, Gage F. Concise Review: The Promise of Human Induced Pluripotent Stem Cell‐Based Studies of Schizophrenia. Stem Cells 2011, 29: 1915-1922. PMID: 22009633, PMCID: PMC3381343, DOI: 10.1002/stem.762.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsGenome-wide association studiesHuman induced pluripotent stem cellsHiPSC neuronsMolecular mechanismsStem cell-based studiesGene expression changesLive human neuronsInduced pluripotent stem cellsPluripotent stem cellsCommon single nucleotide polymorphismsRare copy number variantsCell-based studiesCopy number variantsSingle nucleotide polymorphismsExpression changesAssociation studiesCellular defectsHuman diseasesPost-mortem humanHeritable developmental disorderNumber variantsNucleotide polymorphismsHuman neuronsStem cellsGenesBrief Report: Efficient Generation of Hematopoietic Precursors and Progenitors from Human Pluripotent Stem Cell Lines
Woods N, Parker A, Moraghebi R, Lutz M, Firth A, Brennand K, Berggren W, Raya A, Belmonte J, Gage F, Verma I. Brief Report: Efficient Generation of Hematopoietic Precursors and Progenitors from Human Pluripotent Stem Cell Lines. Stem Cells 2011, 29: 1158-1164. PMID: 21544903, PMCID: PMC3254148, DOI: 10.1002/stem.657.Peer-Reviewed Original ResearchConceptsEmbryonic stem cellsHuman embryonic stem cellsHematopoietic stem cellsHematopoietic progenitorsStem cellsDifferentiation protocolsDefinitive hematopoietic stem cellsHuman pluripotent stem cell linesGeneration of precursorsMultipotent hematopoietic progenitorsIPSC linesStem cell linesPrimitive hematopoietic cellsPluripotent stem cellsPluripotent stem cell lineExtra-cellular matrix componentsEmbryonic developmentHematopoietic progenitor cellsDifferent human embryonic stem cellHematopoietic lineagesDifferentiation culturesHematopoietic potentialCellular matrix componentsNovel factorHematopoietic cellsRapid Cellular Turnover in Adipose Tissue
Rigamonti A, Brennand K, Lau F, Cowan C. Rapid Cellular Turnover in Adipose Tissue. PLOS ONE 2011, 6: e17637. PMID: 21407813, PMCID: PMC3047582, DOI: 10.1371/journal.pone.0017637.Peer-Reviewed Original ResearchConceptsCellular turnoverAdipocyte populationsRapid cellular turnoverGreen fluorescent proteinIndependent experimental approachesIncorporation of BrdUFluorescent proteinMurine adipose tissueRapid turnoverTissue turnoverPossible new avenuesTurnoverAdipose tissueExperimental approachNew avenuesHistones