2020
Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses
Fogaça MV, Wu M, Li C, Li XY, Picciotto MR, Duman RS. Inhibition of GABA interneurons in the mPFC is sufficient and necessary for rapid antidepressant responses. Molecular Psychiatry 2020, 26: 3277-3291. PMID: 33070149, PMCID: PMC8052382, DOI: 10.1038/s41380-020-00916-y.Peer-Reviewed Original ResearchConceptsGABA interneuronsRapid antidepressant responseMajor depressive disorderAntidepressant effectsSynaptic plasticityAntidepressant responseRapid-acting antidepressantsAcetylcholine muscarinic receptor antagonistMuscarinic receptor antagonistCortical brain areasEffects of scopolamineAntidepressant actionChemogenetic inhibitionGABAergic interneuronsReceptor antagonistDepressive disorderMale miceInterneuron subtypesBrain areasInterneuronsMPFCTransient inhibitionAffective behaviorInhibitionSubtypesGABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. Journal Of Clinical Investigation 2020, 130: 1336-1349. PMID: 31743111, PMCID: PMC7269589, DOI: 10.1172/jci130808.Peer-Reviewed Original ResearchConceptsRapid antidepressant actionsAntidepressant actionGABA interneuronsMedial prefrontal cortexCell-specific knockdownPrinciple neuronsPrefrontal cortexDeletion of GluN2BSingle subanesthetic doseBehavioral actionsAction of ketamineNMDA receptor antagonistExcitatory postsynaptic currentsCellular triggersMajor unmet needKetamine's rapid antidepressant actionsGABA subtypeGluN2B-NMDARsSST interneuronsPostsynaptic currentsReceptor antagonistDepressed patientsSubanesthetic doseExtracellular glutamateMood disorders
2019
Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine
Deyama S, Bang E, Wohleb ES, Li XY, Kato T, Gerhard DM, Dutheil S, Dwyer JM, Taylor SR, Picciotto MR, Duman RS. Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine. American Journal Of Psychiatry 2019, 176: 388-400. PMID: 30606046, PMCID: PMC6494682, DOI: 10.1176/appi.ajp.2018.17121368.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, NeutralizingBehavior, AnimalExcitatory Amino Acid AntagonistsGene Knockdown TechniquesGene Knockout TechniquesIn Vitro TechniquesKetamineMiceNeuronsPrefrontal CortexQuinazolinesSignal TransductionVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsNeuronal vascular endothelial growth factorVascular endothelial growth factorMedial prefrontal cortexRapid antidepressant actionsAntidepressant actionIntra-mPFC infusionSystemic ketamineBehavioral actionsFlk-1Conventional monoamine-based antidepressantsPrefrontal cortexRole of VEGFRapid antidepressant effectsTreatment-resistant depressionMethyl-d-aspartate receptor antagonist ketamineNeuron-specific deletionMonoamine-based antidepressantsNeuron-specific knockoutViral-mediated knockdownEndothelial growth factorVEGF-Flk-1Synaptogenic actionsAntidepressant effectsSynaptogenic effectsLocal knockdown
2018
Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor
Deyama S, Bang E, Kato T, Li XY, Duman RS. Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor. Biological Psychiatry 2018, 86: 143-152. PMID: 30712809, PMCID: PMC6597338, DOI: 10.1016/j.biopsych.2018.12.014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, BlockingAntidepressive AgentsBehavior, AnimalBrain-Derived Neurotrophic FactorCerebral CortexGene DeletionMaleMiceMice, Inbred C57BLMicroinjectionsNeuronsNootropic AgentsPrefrontal CortexPrimary Cell CultureVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsBrain-derived neurotrophic factorVascular endothelial growth factorRole of VEGFAntidepressant-like actionPrimary cortical neuronsNeurotrophic actionsEndothelial growth factorMedial prefrontal cortexRelease of VEGFAntidepressant actionCortical neuronsAction of BDNFInfluence of BDNFRole of BDNFRat primary cortical neuronsGrowth factorAntidepressant behavioral actionsNeuron-specific deletionActivity-dependent releaseAction of VEGFBDNF inductionDendrite complexityNeurotrophic factorReceptor antagonistVEGF expressionActivity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine
Fukumoto K, Fogaça M, Liu RJ, Duman C, Kato T, Li XY, Duman RS. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 116: 297-302. PMID: 30559184, PMCID: PMC6320534, DOI: 10.1073/pnas.1814709116.Peer-Reviewed Original ResearchConceptsActivity-dependent BDNF releaseAntidepressant effectsAntidepressant actionBDNF releaseActivity-dependent brain-derived neurotrophic factorL-type voltage-dependent CaSynaptic functionBrain-derived neurotrophic factorMajor depressive disorder patientsMethyl-d-aspartate (NMDA) receptor antagonistIntra-mPFC microinjectionRapid antidepressant effectsDepressive disorder patientsTreatment of MDDBDNF Val66Met allelesVoltage-dependent CaIntra-mPFC infusionMetabolite of ketamineDownstream TrkBNeurotrophic factorReceptor antagonistNMDA receptorsMolecular signaling mechanismsRodent modelsDisorder patientsThe neurotrophic and antidepressant actions of BDNF and VEGF require interactive signaling
Deyama S, Baing E, Kato T, Li X, Duman R. The neurotrophic and antidepressant actions of BDNF and VEGF require interactive signaling. Proceedings For Annual Meeting Of The Japanese Pharmacological Society 2018, WCP2018: po2-1-62. DOI: 10.1254/jpssuppl.wcp2018.0_po2-1-62.Peer-Reviewed Original ResearchBrain-derived neurotrophic factorVascular endothelial growth factorMedial prefrontal cortexAntidepressant actionAntidepressant effectsDendritic complexityNeurotrophic factorCortical neuronsPrimary cultured cortical neuronsNovelty-suppressed feeding testNeuronal vascular endothelial growth factorGrowth factorNeuron-specific deletionCultured cortical neuronsActivity-dependent releasePrimary cortical neuronsEndothelial growth factorIntra-mPFC infusionBDNF-TrkBBDNF receptorAntidepressant responseBDNF infusionSwim testVEGF infusionNeurotrophic responses
2017
BDNF release and signaling are required for the antidepressant actions of GLYX-13
Kato T, Fogaça MV, Deyama S, Li XY, Fukumoto K, Duman RS. BDNF release and signaling are required for the antidepressant actions of GLYX-13. Molecular Psychiatry 2017, 23: 2007-2017. PMID: 29203848, PMCID: PMC5988860, DOI: 10.1038/mp.2017.220.Peer-Reviewed Original ResearchConceptsGLYX-13Antidepressant actionAntidepressant effectsIntra-medial prefrontal cortex infusionN-methyl-d-aspartate modulatorsActivation of VDCCsAntidepressant behavioral actionsConventional antidepressant medicationRapid antidepressant actionsActivity-dependent releaseVoltage-dependent Ca2Partial agonist propertiesPreclinical rodent modelsBDNF Val66Met allelesBDNF-TrkBAntidepressant medicationBDNF releaseGlutamatergic compoundsMonoaminergic systemsDepressed patientsRodent modelsAgonist propertiesVal66Met alleleTherapeutic efficacyMutant mice
2011
Brain-Derived Neurotrophic Factor Val66Met Allele Impairs Basal and Ketamine-Stimulated Synaptogenesis in Prefrontal Cortex
Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-Derived Neurotrophic Factor Val66Met Allele Impairs Basal and Ketamine-Stimulated Synaptogenesis in Prefrontal Cortex. Biological Psychiatry 2011, 71: 996-1005. PMID: 22036038, PMCID: PMC3290730, DOI: 10.1016/j.biopsych.2011.09.030.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsBrain-Derived Neurotrophic FactorDendritesDepressive Disorder, MajorExcitatory Amino Acid AntagonistsExcitatory Postsynaptic PotentialsKetamineMiceMice, TransgenicPatch-Clamp TechniquesPolymorphism, GeneticPrefrontal CortexPyramidal CellsReceptors, N-Methyl-D-AspartateRNA, MessengerSynapsesConceptsBDNF messenger RNAMet miceVal/MetPrefrontal cortexSynaptic deficitsPyramidal cellsBrain-derived neurotrophic factor (BDNF) Val66Met polymorphismNeurotrophic factor Val66Met polymorphismLayer V pyramidal cellsMet alleleDistal apical dendritesExcitatory postsynaptic currentsWhole-cell recordingsPFC pyramidal cellsBDNF Met alleleMet/MetTwo-photon laser scanningMessenger RNAAspartate antagonistAntidepressant actionAntidepressant responseSpine densityVal66Met polymorphismApical dendritesPostsynaptic currentsGlutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS. Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure. Biological Psychiatry 2011, 69: 754-761. PMID: 21292242, PMCID: PMC3068225, DOI: 10.1016/j.biopsych.2010.12.015.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBehavior, AnimalBlotting, WesternChoice BehaviorDendritic SpinesElectrophysiologyExcitatory Amino Acid AntagonistsKetamineNeuronsPhenolsPiperidinesPrefrontal CortexRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSignal TransductionSirolimusStress, PhysiologicalStress, PsychologicalSynapsesSynaptic TransmissionConceptsGlutamate N-methyl-d-aspartate (NMDA) receptor antagonistN-methyl-D-aspartate receptor antagonistNMDA receptor antagonistReceptor antagonistLayer V pyramidal neuronsChronic unpredictable stress modelMammalian targetStress exposureDepressant-like behaviorLong-term stress exposurePathophysiology of depressionRapid antidepressant actionsSelective NMDA receptorChronic stress exposurePrefrontal cortex neuronsAntidepressant actionAcute treatmentChronic administrationSynaptic deficitsPyramidal neuronsSpine densityRo 25Cortex neuronsFunctional deficitsNMDA receptors
2010
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science 2010, 329: 959-964. PMID: 20724638, PMCID: PMC3116441, DOI: 10.1126/science.1190287.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntidepressive AgentsDendritic SpinesDepressionIntracellular Signaling Peptides and ProteinsKetamineMaleNeuronsNeuropeptidesPhenolsPiperidinesProtein BiosynthesisProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSignal TransductionSirolimusSynapsesTime FactorsTOR Serine-Threonine KinasesConceptsTreatment-resistant depressed patientsBlockade of mTORFast antidepressant actionAction of ketamineRapid antidepressant effectsRapid antidepressant responseEffects of ketamineModel of depressionAntidepressant actionAntidepressant effectsAntidepressant responseKetamine inductionStandard medicationSynaptic deficitsKetamine administrationDepressed patientsSpine synapsesNMDA antagonistsMood disordersSynapse formationKetamineMammalian targetPrefrontal cortexRapamycin (mTOR) pathwayPossible new approach
2009
Eszopiclone and fluoxetine enhance the survival of newborn neurons in the adult rat hippocampus
Su XW, Li XY, Banasr M, Duman RS. Eszopiclone and fluoxetine enhance the survival of newborn neurons in the adult rat hippocampus. The International Journal Of Neuropsychopharmacology 2009, 12: 1421-1428. PMID: 19775501, PMCID: PMC3677220, DOI: 10.1017/s1461145709990629.Peer-Reviewed Original ResearchConceptsNewborn neuronsAntidepressant actionSerotonin uptake inhibitorAdult rat hippocampusAdult hippocampusCombined administrationDorsal hippocampusRat hippocampusPreclinical studiesAdult ratsUptake inhibitorFluoxetineHippocampusNewborn cellsClinical researchEszopicloneBehavioral actionsNeuronsSurvivalAdditive effectNovel mechanismProliferationAntidepressantsPatientsChronic