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
2018
Neurophysiological signals as predictive translational biomarkers for Alzheimer’s disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats
Stoiljkovic M, Kelley C, Horvath TL, Hajós M. Neurophysiological signals as predictive translational biomarkers for Alzheimer’s disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats. Alzheimer's Research & Therapy 2018, 10: 105. PMID: 30301466, PMCID: PMC6178257, DOI: 10.1186/s13195-018-0433-4.Peer-Reviewed Original ResearchConceptsTgF344-AD ratsWild-type ratsEffects of donepezilOscillatory abnormalitiesTgF344-ADStimulation-induced hippocampal theta oscillationAdult wild-type ratsDisease pathologyAccumulation of amyloidHigh-voltage spindle activityDisease-modifying potentialSeizure-like activityAlzheimer's disease pathologySpontaneous cortical activityAge-dependent reductionDisease treatmentHigh-voltage spindlesAcetylcholine esterase inhibitorsNeuronal network oscillationsAlzheimer's disease treatmentHippocampal theta oscillationsDonepezil treatmentCholinergic toneUrethane anesthesiaClinical effectivenessAltered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer’s Disease Pathology
Stoiljkovic M, Kelley C, Stutz B, Horvath TL, Hajós M. Altered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer’s Disease Pathology. Cerebral Cortex 2018, 29: 2716-2727. PMID: 29920597, PMCID: PMC7302691, DOI: 10.1093/cercor/bhy140.Peer-Reviewed Original ResearchConceptsTgF344-AD ratsHippocampal theta oscillationsAlzheimer's diseaseDisease pathologyTheta-phase gamma-amplitude couplingAge-matched wild-type counterpartsAD pathological featuresDisease-modifying therapiesAccumulation of amyloidPredictive animal modelsAlzheimer's disease pathologyHigh-voltage spindlesTheta oscillationsSignificant age-dependent declineAge-dependent declineHippocampal excitabilitySharp-wave ripplesAβ accumulationNeuronal lossAD ratsPathological featuresUrethane anesthesiaAD patientsAuditory gatingAD drugs
2016
Activation of α7 nicotinic acetylcholine receptors facilitates long-term potentiation at the hippocampal-prefrontal cortex synapses in vivo
Stoiljkovic M, Kelley C, Nagy D, Hurst R, Hajós M. Activation of α7 nicotinic acetylcholine receptors facilitates long-term potentiation at the hippocampal-prefrontal cortex synapses in vivo. European Neuropsychopharmacology 2016, 26: 2018-2023. PMID: 27866776, DOI: 10.1016/j.euroneuro.2016.11.003.Peer-Reviewed Original ResearchConceptsHippocampal-medial prefrontal cortex pathwayHippocampal-prefrontal cortex pathwayLong-term potentiationPrefrontal cortex pathwayCognitive processesCortex pathwayCognitive effectsMnemonic functionsCognitive functionMemory formationNeurophysiological effectsΑ7-nAChR activationNAChR activationΑ7 nAChRsHippocampal long-term potentiationSubiculum regionsΑ7 nicotinic acetylcholine receptorNicotinic acetylcholine receptorsMale ratsSaline controlsSynaptic transmissionBrain slicesTetanic stimulationAcetylcholine receptorsSynaptic plasticitySelective 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 activityΑ7Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice
Stoiljkovic M, Kelley C, Hajós GP, Nagy D, Koenig G, Leventhal L, Hajós M. Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice. Neurobiology Of Aging 2016, 45: 161-168. PMID: 27459936, DOI: 10.1016/j.neurobiolaging.2016.05.021.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseΑ7 nicotinic acetylcholine receptorEffect of α7Wild-type miceGamma oscillationsNicotinic acetylcholine receptorsHippocampal network dynamicsSymptomatic treatmentClinical findingsAD patientsSaline controlsProcognitive drugsΑ7 nAChRsTransgenic miceAcetylcholine receptorsReceptor activationCognitive functionHippocampal oscillationsMiceNeurophysiological impairmentsAgonistsPower of thetaΑ7AβSignificant differences
2015
Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy
Nagy D, Stoiljkovic M, Menniti FS, Hajós M. Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy. Neuropsychopharmacology 2015, 41: 1486-1494. PMID: 26404843, PMCID: PMC4832008, DOI: 10.1038/npp.2015.298.Peer-Reviewed Original ResearchConceptsAuditory-evoked potentialsAntidepressant effectsSynaptic potentiationAntidepressant efficacyAuditory gatingRapid-onset antidepressant effectsEffects of ketaminePrimary auditory cortexReceptor channel blockerDifferent acute effectsNMDA receptor inhibitionNegative allosteric modulatorsPotential mechanistic underpinningsReceptor inhibitionSystemic administrationAcute effectsNeurophysiological biomarkersTranslatable biomarkersChannel blockersDrug eliminationAuditory cortexNeurophysiological parametersDrug AdministrationGamma band powerKetamineModulation of hippocampal neuronal network oscillations by α7 nACh receptors
Stoiljkovic M, Kelley C, Nagy D, Hajós M. Modulation of hippocampal neuronal network oscillations by α7 nACh receptors. Biochemical Pharmacology 2015, 97: 445-453. PMID: 26206189, DOI: 10.1016/j.bcp.2015.06.031.Peer-Reviewed Original ResearchConceptsNucleus pontis oralisNeuronal network oscillationsΑ7 nAChRsHippocampal oscillationsNetwork oscillationsBrainstem nucleus pontis oralisHippocampal-dependent cognitive functionsHippocampal thetaTheta-phase gamma-amplitude couplingΑ7 nicotinic acetylcholine receptorHigh-frequency stimulationΑ7 nACh receptorsNicotinic acetylcholine receptorsNeuronal network activityNetwork activityPyramidal neuronsFrequency stimulationPontis oralisPharmacological effectsPreclinical screeningNACh receptorsAcetylcholine receptorsSuch drugsCognitive functionHippocampusConcentration-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
2008
Local antagonism of intertrigeminal region metabotropic glutamate receptors exacerbates apneic responses to intravenous serotonin
Stoiljkovic M, Radulovacki M, Carley D. Local antagonism of intertrigeminal region metabotropic glutamate receptors exacerbates apneic responses to intravenous serotonin. Respiratory Physiology & Neurobiology 2008, 165: 137-142. PMID: 19026767, PMCID: PMC2773821, DOI: 10.1016/j.resp.2008.10.019.Peer-Reviewed Original ResearchConceptsIntravenous serotonin infusionMetabotropic glutamate receptorsIntertrigeminal regionSerotonin infusionReceptor antagonistGlutamate receptorsBroad-spectrum glutamate receptor antagonistType 1 metabotropic glutamate receptorMetabotropic glutamate antagonistPontine intertrigeminal regionVagal afferent pathwaysDuration of apneaGlutamate receptor antagonistsAMPA receptor antagonistDose-dependent fashionRespiratory pattern changesApnea expressionApneic responseIntravenous serotoninSpontaneous apneasReflex apneaRespiratory dysrhythmiaAfferent pathwaysIntravenous infusionGlutamate antagonists
2006
Effects of intertrigeminal region NMDA and non-NMDA receptors on respiratory responses in rats
Radulovacki M, Stoiljkovic M, Saponjic J, Carley D. Effects of intertrigeminal region NMDA and non-NMDA receptors on respiratory responses in rats. Respiratory Physiology & Neurobiology 2006, 156: 40-46. PMID: 16934539, DOI: 10.1016/j.resp.2006.07.005.Peer-Reviewed Original ResearchConceptsNon-NMDA receptorsIntertrigeminal regionNMDA receptorsReflex apneaNonspecific glutamate receptor antagonist kynurenic acidGlutamate receptor antagonist kynurenic acidSpecific NMDA receptor antagonistRespiratory responsesAntagonist kynurenic acidVentral respiratory groupMicroinjection of glutamateNMDA receptor antagonistSleep-related apneaLong-term potentiationFunctional NMDA receptorsImmediate apneaVagal reflexGlutamate injectionRespiratory groupRespiratory disturbancesKynurenic acidReceptor antagonistSelective blockadeApneaLateral pons