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
2024
Aligning Stem Cell Models and Postmortem Studies to Query Striatal Neurodevelopment in Schizophrenia
Brennand K. Aligning Stem Cell Models and Postmortem Studies to Query Striatal Neurodevelopment in Schizophrenia. American Journal Of Psychiatry 2024, 181: 465-467. PMID: 38822585, DOI: 10.1176/appi.ajp.20240245.Peer-Reviewed Original Research
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
Prenatal Δ9-Tetrahydrocannabinol Exposure in Males Leads to Motivational Disturbances Related to Striatal Epigenetic Dysregulation
Ellis R, Bara A, Vargas C, Frick A, Loh E, Landry J, Uzamere T, Callens J, Martin Q, Rajarajan P, Brennand K, Ramakrishnan A, Shen L, Szutorisz H, Hurd Y. Prenatal Δ9-Tetrahydrocannabinol Exposure in Males Leads to Motivational Disturbances Related to Striatal Epigenetic Dysregulation. Biological Psychiatry 2021, 92: 127-138. PMID: 34895699, PMCID: PMC8957623, DOI: 10.1016/j.biopsych.2021.09.017.Peer-Reviewed Original ResearchConceptsEpigenetic dysregulationNucleus accumbensSimilar transcriptional alterationsExpression of Kmt2aComparison of RNACellular chromatinTranscriptome datasetsPrenatal THC exposureEpigenetic signaturesEpigenetic profilesAdult male offspringHuman major depressive disorderRNA sequencingTranscriptional alterationsSequencing approachPrenatal cannabis exposureMajor depressive disorderΔ9-tetrahydrocannabinol exposurePrincipal psychoactive componentMolecular signaturesUnbiased sequencing approachRat offspringUtero exposureTHC exposureCannabis exposureFitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes
Ikegame S, Hashiguchi T, Hung C, Dobrindt K, Brennand K, Takeda M, Lee B. Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2026027118. PMID: 33903248, PMCID: PMC8106313, DOI: 10.1073/pnas.2026027118.Peer-Reviewed Original ResearchConceptsF mutantsMeasles inclusion body encephalitisBSR-T7 cellsMeasles virus F proteinReceptor-binding proteinVirus F proteinGenomic contextFitness advantageWild-type MeVRegulatory domainHyperfusogenic phenotypePrimary human neuronsMutant libraryPoint mutantsMutantsFitness selectionMeV receptorsF phenotypeInclusion body encephalitisNeuropathogenic phenotypeFitness landscapeChronic latent infectionFusion geneF proteinHuman neuronsXenopus models suggest convergence of gene signatures on neurogenesis in autism
Brennand K, Talkowski M. Xenopus models suggest convergence of gene signatures on neurogenesis in autism. Neuron 2021, 109: 743-745. PMID: 33662268, DOI: 10.1016/j.neuron.2021.02.017.Commentaries, Editorials and LettersCommon Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection
Dobrindt K, Hoagland DA, Seah C, Kassim B, O'Shea CP, Murphy A, Iskhakova M, Fernando MB, Powell SK, Deans PJM, Javidfar B, Peter C, Møller R, Uhl SA, Garcia MF, Kimura M, Iwasawa K, Crary JF, Kotton DN, Takebe T, Huckins LM, tenOever BR, Akbarian S, Brennand KJ. Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection. Stem Cell Reports 2021, 16: 505-518. PMID: 33636110, PMCID: PMC7881728, DOI: 10.1016/j.stemcr.2021.02.010.Peer-Reviewed Original ResearchMeSH Keywords3' Untranslated RegionsAdolescentAdultAnimalsCell LineChlorocebus aethiopsClustered Regularly Interspaced Short Palindromic RepeatsCOVID-19FemaleFurinGenetic Predisposition to DiseaseHost-Pathogen InteractionsHumansInduced Pluripotent Stem CellsMaleNeuronsPeptide HydrolasesPolymorphism, Single NucleotideSARS-CoV-2Vero CellsConceptsSARS-CoV-2Clinical complicationsSARS-CoV-2 infectionCommon genetic variationHigh-risk individualsHost genetic variantsSignificant interindividual variabilityNeuron infectionUnderlying comorbiditiesViral loadHealthy individualsViral infectionClinical heterogeneityVitro SusceptibilityEtiologic agentHost responseInterindividual variabilityDiscovery of drugsInfectionHost geneticsHuman induced pluripotent stem cellsSingle nucleotide polymorphismsAntibody repertoireMore diseasesComplicationsMolecular 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
Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer’s Disease
Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, Fernando MB, Yu A, Zhu L, Cao J, Lyu L, Horgusluoglu E, Wang Q, Guo L, Wang YS, Neff R, Song WM, Wang E, Shen Q, Zhou X, Ming C, Ho SM, Vatansever S, Kaniskan HÜ, Jin J, Zhou MM, Ando K, Ho L, Slesinger PA, Yue Z, Zhu J, Katsel P, Gandy S, Ehrlich ME, Fossati V, Noggle S, Cai D, Haroutunian V, Iijima KM, Schadt E, Brennand KJ, Zhang B. Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer’s Disease. Neuron 2020, 109: 257-272.e14. PMID: 33238137, PMCID: PMC7855384, DOI: 10.1016/j.neuron.2020.11.002.Peer-Reviewed Original ResearchConceptsLate-onset Alzheimer's diseaseAlzheimer's diseaseKey regulatorPluripotent stem cell-derived neuronsRNAi-based knockdownStem cell-derived neuronsNovel therapeutic targetNext-generation therapeutic agentsCell-derived neuronsKey brain regionsIntegrative network analysisMulti-omics dataComplex molecular interactionsMulti-omics profilingNCH-51Neuronal impairmentGene subnetworksDisease-related processesCortical areasTherapeutic targetDrosophila modelNeuropathological phenotypeBrain regionsTherapeutic agentsMolecular mechanismsIntegration of CRISPR-engineering and hiPSC-based models of psychiatric genomics
Matos MR, Ho SM, Schrode N, Brennand KJ. Integration of CRISPR-engineering and hiPSC-based models of psychiatric genomics. Molecular And Cellular Neuroscience 2020, 107: 103532. PMID: 32712198, PMCID: PMC7484226, DOI: 10.1016/j.mcn.2020.103532.Peer-Reviewed Original ResearchConceptsPenetrant rare variantsDisease-associated variantsNeuronal cell typesPluripotent stem cellsGenomic engineeringFunctional characterizationComplex geneticsCRISPR engineeringCRISPR technologyIsogenic comparisonsPsychiatric genomicsCell typesGenetic variantsStem cellsIndividual variantsCommon variantsPolygenic disorderRare variantsVariantsComplex interplayGenomicsGenetic riskPleiotropyCRISPRGeneticsCell 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 regionModeling the complex genetic architectures of brain disease
Fernando MB, Ahfeldt T, Brennand KJ. Modeling the complex genetic architectures of brain disease. Nature Genetics 2020, 52: 363-369. PMID: 32203467, PMCID: PMC7909729, DOI: 10.1038/s41588-020-0596-3.Peer-Reviewed Original ResearchConceptsGenetic architectureComplex genetic architectureFunctional validation studiesRelevant disease biologyIntersection of genomicsComplex genetic diseasesCombination of genesPluripotent stem cellsGene perturbationsIsogenic comparisonsMolecular mechanismsPhenotypic drug discoveryCell typesGenetic diseasesFunctional consequencesGenetic backgroundRisk variantsStem cellsCRISPRDisease biologyDrug discoveryRare variantsConfer riskGenetic diagnosisVariantsA 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
2019
Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs
Halpern M, Brennand KJ, Gregory J. Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs. Neurobiology Of Disease 2019, 132: 104562. PMID: 31381978, PMCID: PMC6834907, DOI: 10.1016/j.nbd.2019.104562.Peer-Reviewed Original ResearchConceptsAmyotrophic lateral sclerosisAstrocyte dysfunctionNeurodegenerative diseasesRole of astrocytesNon-cell autonomous mechanismsFatal neurodegenerative diseaseRisk-associated genesAstrocytic dysfunctionNeural cell typesAstrocyte functionDisease onsetDisease progressionMotor neuronsLateral sclerosisTherapeutic interventionsDysfunctionDisease initiationGenetic factorsPotential targetProgressionAutonomous mechanismsDiseaseStem cellsNeurodegenerationCell typesSpatial genome exploration in the context of cognitive and neurological disease
Rajarajan P, Borrman T, Liao W, Espeso-Gil S, Chandrasekaran S, Jiang Y, Weng Z, Brennand KJ, Akbarian S. Spatial genome exploration in the context of cognitive and neurological disease. Current Opinion In Neurobiology 2019, 59: 112-119. PMID: 31255842, PMCID: PMC6889018, DOI: 10.1016/j.conb.2019.05.007.Peer-Reviewed Original ResearchConceptsGenome explorationSpecific gene expression programsImportant regulatory layerTopological chromatin domainsGene expression programsChromosomal contact mapsChromatin domainsGenome organizationExpression programsRegulatory layerTranscriptional regulationChromosomal contactsWidespread remodelingTranscriptomic analysisRepeat sequencesUnexpected linkNeuronal lineageNeural differentiationNon-contiguous sequencesContact mapsAbnormal expansionNeurodegenerative diseasesNew insightsSequenceMouse brain
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