2022
LINE-1 activation in the cerebellum drives ataxia
Takahashi T, Stoiljkovic M, Song E, Gao XB, Yasumoto Y, Kudo E, Carvalho F, Kong Y, Park A, Shanabrough M, Szigeti-Buck K, Liu ZW, Kristant A, Zhang Y, Sulkowski P, Glazer PM, Kaczmarek LK, Horvath TL, Iwasaki A. LINE-1 activation in the cerebellum drives ataxia. Neuron 2022, 110: 3278-3287.e8. PMID: 36070749, PMCID: PMC9588660, DOI: 10.1016/j.neuron.2022.08.011.Peer-Reviewed Original ResearchConceptsLINE-1 activationL1 activationAtaxia telangiectasia patientsNuclear element-1Transposable elementsEpigenetic silencersHuman genomeL1 promoterMolecular regulatorsDNA damagePurkinje cell dysfunctionElement 1First direct evidenceTelangiectasia patientsDirect targetingCerebellar expressionNeurodegenerative diseasesDisease etiologyCalcium homeostasisTREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice
Stoiljkovic M, Gutierrez KO, Kelley C, Horvath TL, Hajós M. TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice. Journal Of Alzheimer's Disease 2022, 88: 837-847. PMID: 34120899, PMCID: PMC8898080, DOI: 10.3233/jad-210041.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseMicroglial functionTREM2 functionTheta-phase gamma-amplitude couplingHippocampal network functionSpontaneous epileptiform seizuresNetwork oscillationsTransgenic AD modelHippocampal neuronal excitabilityMyeloid cells 2Clinical Alzheimer's diseaseWild-type miceHippocampal network oscillationsHippocampal pathophysiologyProgressive dementiaTau pathologyUrethane anesthesiaAD pathophysiologyNeuronal excitabilityEpileptiform seizuresEpileptic activityAD modelTREM2Disease pathologyCells 2AgRP neurons control structure and function of the medial prefrontal cortex
Stutz B, Waterson MJ, Šestan-Peša M, Dietrich MO, Škarica M, Sestan N, Racz B, Magyar A, Sotonyi P, Liu ZW, Gao XB, Matyas F, Stoiljkovic M, Horvath TL. AgRP neurons control structure and function of the medial prefrontal cortex. Molecular Psychiatry 2022, 27: 3951-3960. PMID: 35906488, PMCID: PMC9891653, DOI: 10.1038/s41380-022-01691-8.Peer-Reviewed Original ResearchConceptsMedial prefrontal cortexAgRP neuronsNon-selective dopamine receptor antagonistBrain functionPrefrontal cortexHypothalamic AgRP neuronsMedial thalamic neuronsAdministration of clozapineDopamine receptor antagonistVentral tegmental areaOscillatory network activityHigher-order brain functionsHypothalamic agoutiThalamic neuronsChemogenetic inhibitionDopaminergic neuronsReceptor antagonistTegmental areaNeuronal pathwaysSensorimotor gatingAdult miceModulatory impactAmbulatory behaviorConstitutive impairmentNeurons
2021
Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior
Yasumoto Y, Stoiljkovic M, Kim JD, Sestan-Pesa M, Gao XB, Diano S, Horvath TL. Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior. Molecular Psychiatry 2021, 26: 2740-2752. PMID: 33879866, PMCID: PMC8056795, DOI: 10.1038/s41380-021-01105-1.Peer-Reviewed Original ResearchConceptsAnxiety-like behaviorReactive oxygen speciesMicroglia-synapse contactsSpine synapse numberHippocampal circuit functionNeuronal circuit dysfunctionMicroglial productionVentral hippocampusCircuit dysfunctionSpine synapsesSynapse numberAdult brainTransient riseMitochondrial ROS generationMicrogliaBrain functionConditional ablationPhagocytic inclusionsSynaptic elementsProtein 2ROS generationSignificant reductionCircuit functionConsequent accumulationOxygen speciesCerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1
Zhang Y, Varela L, Szigeti-Buck K, Williams A, Stoiljkovic M, Šestan-Peša M, Henao-Mejia J, D’Acunzo P, Levy E, Flavell RA, Horvath TL, Kaczmarek LK. Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1. Nature Communications 2021, 12: 1731. PMID: 33741962, PMCID: PMC7979925, DOI: 10.1038/s41467-021-22003-8.Peer-Reviewed Original ResearchConceptsTank Binding Kinase 1HAX-1Kv3.3 potassium channelMultivesicular bodiesKinase 1TANK-binding kinase 1Activation of caspasesAnti-apoptotic proteinsPotassium channelsMembrane proteinsBiochemical pathwaysCerebellar neuronsChannels bindCell deathTBK1 activityIon channelsMutant channelsCellular constituentsTraffickingKv3.3 channelsProteinNeuronal survivalMutationsChannel inactivationCaspases
2020
Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice
Tan Y, Hang F, Liu ZW, Stoiljkovic M, Wu M, Tu Y, Han W, Lee AM, Kelley C, Hajos M, Lu L, de Lecea L, de Araujo I, Picciotto M, Horvath TL, Gao XB. Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice. Journal Of Clinical Investigation 2020, 130: 4985-4998. PMID: 32516139, PMCID: PMC7456212, DOI: 10.1172/jci130889.Peer-Reviewed Original ResearchConceptsHcrt cellsObese miceDiet-induced obese miceObese male miceExcessive energy intakeNeuropeptide hypocretin/orexinHypocretin/orexinHcrt neuronsMale miceHcrt systemClinical studiesCommon causeSynaptic transmissionObese animalsEnergy intakeAcute stressCognitive functionSalient stimuliAlters responsesExact mechanismMiceHomeostatic regulationNeuronal networksBehavioral changesNeurons
2019
Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice
Nagy D, Martens LH, Leventhal L, Chen A, Kelley C, Stoiljkovic M, Hajós M. Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice. Alzheimer's Research & Therapy 2019, 11: 88. PMID: 31639062, PMCID: PMC6805349, DOI: 10.1186/s13195-019-0540-x.Peer-Reviewed Original ResearchConceptsHomozygous miceProgranulin deficiencyBehavioral abnormalitiesFrontotemporal dementiaAge-dependent emergenceHuman frontotemporal dementiasProgranulin-deficient miceExtensive neuronal lossAge-dependent deficitsPaired-pulse depressionHeterogeneous neurodegenerative disorderNeuronal lossVivo electrophysiologyCortical pathwaysThalamocortical circuitsTemporal lobeSynaptic connectivityBehavioral alterationsConclusionOur findingsNeurodegenerative disordersMiceFunction mutationsAge 3DementiaAbnormalities
2016
Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations
Stoiljkovic M, Kelley C, Nagy D, Leventhal L, Hajós M. Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations. Neuropharmacology 2016, 110: 102-108. PMID: 27422408, DOI: 10.1016/j.neuropharm.2016.07.010.Peer-Reviewed Original ResearchConceptsΑ7 nicotinic acetylcholine receptorNicotinic acetylcholine receptorsΑ7 nAChRsHippocampal oscillationsPNU-282987Acetylcholine receptorsAlzheimer's diseasePotential pharmacologic targetWild-type miceSelective activationNeuronal network oscillationsTheta powerΑ7KO miceHippocampal theta oscillationsClinical evidenceControl micePreclinical observationsUrethane anesthesiaProcognitive activityProcognitive effectsPharmacologic targetAgonistsCognitive deficitsHippocampal activityΑ7
2015
Concentration-response relationship of the α7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays
Stoiljkovic M, Leventhal L, Chen A, Chen T, Driscoll R, Flood D, Hodgdon H, Hurst R, Nagy D, Piser T, Tang C, Townsend M, Tu Z, Bertrand D, Koenig G, Hajós M. Concentration-response relationship of the α7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays. Biochemical Pharmacology 2015, 97: 576-589. PMID: 26206187, DOI: 10.1016/j.bcp.2015.07.006.Peer-Reviewed Original ResearchMeSH KeywordsAlpha7 Nicotinic Acetylcholine ReceptorAnimalsBehavior, AnimalCHO CellsCricetinaeCricetulusDose-Response Relationship, DrugFemaleGene Expression RegulationHippocampusHumansLearningMaleMemoryMiceMice, Inbred C57BLOocytesProtein BindingQuinuclidinesRatsRats, Sprague-DawleyRats, WistarThiophenesXenopus laevisConceptsHippocampal theta oscillationsTheta oscillationsNeurophysiological assaysPro-cognitive effectsNovel object recognitionStimulation-induced hippocampal theta oscillationTheta oscillation powerWater T-mazeCognitive effectsNeurophysiological correlatesDose-dependent facilitationMemory acquisitionCognitive functionT-mazeObject recognitionΑ7 nAChRsHuman α7 nAChRConcentration-response relationshipSynaptic transmissionΑ7 nicotinic acetylcholine receptorSub-maximal concentrationsRat hippocampal slicesLong-term potentiationNicotinic acetylcholine receptorsOscillation power
2014
Application of neurophysiological biomarkers for Huntington's disease: Evaluating a phosphodiesterase 9A inhibitor
Nagy D, Tingley FD, Stoiljkovic M, Hajós M. Application of neurophysiological biomarkers for Huntington's disease: Evaluating a phosphodiesterase 9A inhibitor. Experimental Neurology 2014, 263: 122-131. PMID: 25315303, DOI: 10.1016/j.expneurol.2014.10.001.Peer-Reviewed Original ResearchMeSH Keywords3',5'-Cyclic-AMP PhosphodiesterasesAcoustic StimulationAnimalsAuditory CortexDisease Models, AnimalElectrophysiologyEnzyme InhibitorsEvoked Potentials, AuditoryHippocampusHuntington DiseaseMiceMice, Inbred C57BLMice, TransgenicPyrazolesPyrimidinonesRatsRats, Sprague-DawleyRats, TransgenicSensory GatingConceptsBACHD transgenic ratsPrimary auditory cortexAuditory gatingDisease patientsHuntington's diseaseAuditory cortexBACHD ratsTransgenic ratsPF-04447943Sub-chronic treatmentPotential translational biomarkersHuntington's disease patientsTransgenic animal modelsBasic neuropathologyDaily administrationTranslational biomarkersQ175 miceNeurophysiological abnormalitiesSystemic administrationNeurophysiological biomarkersLast treatmentAnimal modelsTransgenic miceGamma band powerBrain regions