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Principal Investigator: LISA M MONTEGGIA
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $532,105
Funding agency: National Institute of Mental Health
Project Summary
In the previous funding period we investigated the mechanism of rapid antidepressant activity of ketamine, an
ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist. We demonstrated that Brain-
derived neurotrophic factor (BDNF), and its high affinity receptor TrkB, are required for the rapid
antidepressant effects of ketamine as these effects are lost in forebrain specific BDNF knockout mice and
conditional forebrain specific TrkB knockout mice. We found the antidepressant effects of ketamine require
protein translation, but not transcription, resulting in increases in BDNF protein levels in the hippocampus that
are critical for the behavioral effect. Ketamine's blockade of spontaneous NMDA receptor mediated
neurotransmission inactivates eukaryotic elongation factor 2 kinase (eEF2K) resulting in dephosphorylation of
its only known substrate, eukaryotic elongation factor 2, thereby increasing protein translation of target
transcripts, including BDNF. In turn, BDNF is postulated to act via eliciting insertion of 3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptors at the postsynaptic membrane, which results in potentiation of
AMPA receptor-mediated CA3-CA1 field excitatory postsynaptic potentials (fEPSPs) by ketamine. While this
potentiation is suggested to be a cellular correlate of rapid antidepressant effects, its properties deviate from
classical Hebbian forms of plasticity and rather coincide with homeostatic synaptic scaling seen after activity
suppression. These data provide the basis for the novel hypothesis that BDNF-TrkB signaling regulates
synaptic scaling in vivo that is critical for the rapid antidepressant effects of ketamine. The objective of this
renewal is to specifically test the causal and instructive role of BDNF-TrkB signaling in the hippocampus in
ketamine-mediated synaptic scaling and rapid antidepressant effects. Collectively, this information will provide
novel information on the synaptic locus, as well as key molecules, necessary for ketamine's rapid
antidepressant effects.
Terms: <AMPA Receptors><Acids><Acute><Affect><Affinity><Ammon Horn><Animals><Attenuated><BDNF><BDNF Receptor><BDNF/NT-3 Growth Factors Receptor><Behavior><Behavioral><Brain><Brain Nervous System><Brain-Derived Neurotrophic Factor><Brain-Derived Neurotrophic Factor Receptor><C57BL/6 Mouse><CAM kinase III><CNS plasticity><Cam PK III><Cell Communication and Signaling><Cell Signaling><Chemosensitization><Chemosensitization/Potentiation><Chronic><Clinical><Cornu Ammonis><Cytoplasmic Elongation Factor 2><Data><Dephosphorylation><Depressed mood><Development><E-2 kinase><EF-2 kinase><EPSP><Electrophysiology><Electrophysiology (science)><Elongation Factor 2><Encephalon><Eukaryotic Translation Elongation Factor 2><Excitatory Postsynaptic Potentials><Fore-Brain><Forebrain><Funding><GP145-TRKB><Genetic Polymorphism><Glutamates><Grant><Hippocampus><In Vitro><Infusion><Infusion procedures><Intracellular Communication and Signaling><KO mice><Ketamine><Knock-out Mice><Knockout Mice><L-Glutamate><Link><Mediating><Mediator><Mental Depression><Mice><Mice Mammals><Molecular><Murine><Mus><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-Aspartate Receptors><N-Methyl-D-aspartate><N-Methylaspartate><N-Methylaspartate Receptors><NMDA><NMDA Receptor-Ionophore Complex><NMDA Receptors><NSP 100><NSP100><NTRK2 Receptor><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neural Transmission><Neurocyte><Neuronal Plasticity><Neuronal Transmission><Neurons><Neurophysiology / Electrophysiology><Neurotrophic Tyrosine Kinase Receptor Type 2><Null Mouse><Patients><Peptide Elongation Factor 2><Phosphorylation><Polypeptidyl-tRNA Translocase><Postsynaptic Membrane><Potentiation><Pre-Clinical Model><Preclinical Models><Predisposition><Property><Prosencephalon><Protein Dephosphorylation><Protein Phosphorylation><Proteins><Receptor Activation><Receptor Protein><Regulation><Research><Rest><Role><Signal Transduction><Signal Transduction Systems><Signaling><Susceptibility><Synapses><Synaptic><Synaptic Transmission><Synaptic plasticity><TRKB Tyrosine Kinase><Testing><Transcript><Translational Derepression><Translations><Wild Type Mouse><Work><antagonism><antagonist><anti-depressant agent><anti-depressant drugs><anti-depressant effect><anti-depressants><anti-depressive agents><antidepressant effect><attenuate><attenuates><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><calmodulin-dependent protein kinase III><central nervous system plasticity><channel blockers><clinical efficacy><depressed><depression><developmental><eEF-2-specific Ca and calmodulin-dependent protein kinase III><electrophysiological><elongation factor 2 kinase><glia signaling><glial signaling><glutamatergic><hippocampal><in vivo><infusions><insight><kinase inhibitor><nerve signaling><neural plasticity><neural signaling><neuronal><neuronal signaling><neuroplastic><neuroplasticity><neurotransmission><neurotrophic factor><neurotrophin><neutrophin><novel><polymorphism><protein kinase CPK3><receptor><response><sadness><sensor><social role><synapse><synapse function><synaptic function><translation><treatment-refractory depression><treatment-resistant depression><trkB Receptor><trkB(gp145) Protein><wildtype mouse>