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) is required for the fast acting antidepressant effects of ketamine as these effects are lost in forebrain specific BDNF knockout mice. We found that the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels in the hippocampus that are important for the behavioral effect. Recent work has suggested a strong causal link between blockade of resting NMDA receptor activation and rapid increases in local dendritic protein translation. Blockade of NMDA receptor activation by spontaneous glutamate release has been shown to inactive eukaryotic elongation factor 2 kinase resulting in dephosphorylation of its only known substrate, eukaryotic elongation factor 2 (eEF2), thereby increasing protein translation of target transcripts. We showed that ketamine causes a decrease in phosphorylation of eEF2, which normally impedes translation in its phosphorylated state, suggesting translational de-repression of BDNF mRNA. Moreover, inhibitors of eEF2 kinase trigger a rapid antidepressant-like effect in mice and ketamine does not elicit an antidepressant effect in eEF2 kinase null mice. These data provide the basis for the novel hypothesis that ketamine, by blocking NMDA receptors at rest, inhibits the phosphorylation of eEF2 and augments subsequent expression of BDNF, critical determinants of ketamine-mediated antidepressant efficacy. The objective of this renewal is to delineate the role of BDNF-TrkB signaling in the hippocampus in ketamine-mediated antidepressant effects, as well as how eEF2 kinase acts as a transducer between NMDA receptor activity and BDNF regulation. Collectively, this information will provide novel information on the synaptic locus, as well as the key molecules, necessary for ketamine's rapid antidepressant effects.

Public Health Relevance

The objective of this grant is to study the role of BDNF in the hippocampus in mediating antidepressant responses in mice. Based on our preliminary data presented in this application, we will examine the role of the eEF2 signaling pathway in mediating fast acting antidepressant responses upstream of BDNF as well as the impact of BDNF specifically in the hippocampus on rapid antidepressant responses. These studies will use molecular, cellular, behavioral, and electrophysiological approaches to investigate the signaling pathways involved in mediating fast acting antidepressant responses, in the hopes of developing novel antidepressants with rapid onset of clinical efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH070727-12
Application #
9247841
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57)S)
Program Officer
Winsky, Lois M
Project Start
2005-07-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
12
Fiscal Year
2017
Total Cost
$499,712
Indirect Cost
$190,073
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Horvath, Patricia M; Monteggia, Lisa M (2018) MeCP2 as an Activator of Gene Expression. Trends Neurosci 41:72-74
Monteggia, Lisa M; Lin, Pei-Yi; Adachi, Megumi et al. (2018) Behavioral Analysis of SNAP-25 and Synaptobrevin-2 Haploinsufficiency in Mice. Neuroscience :
Crawford, Devon C; Ramirez, Denise M O; Trauterman, Brent et al. (2017) Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy. Nat Commun 8:14436
Horvath, Patricia M; Kavalali, Ege T; Monteggia, Lisa M (2017) CRISPR/Cas9 system-mediated impairment of synaptobrevin/VAMP function in postmitotic hippocampal neurons. J Neurosci Methods 278:57-64
Adachi, Megumi; Autry, Anita E; Mahgoub, Melissa et al. (2017) TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior. Neuropsychopharmacology 42:886-894
Ramirez, Denise M O; Crawford, Devon C; Chanaday, Natali L et al. (2017) Loss of Doc2-Dependent Spontaneous Neurotransmission Augments Glutamatergic Synaptic Strength. J Neurosci 37:6224-6230
Björkholm, Carl; Monteggia, Lisa M (2016) BDNF - a key transducer of antidepressant effects. Neuropharmacology 102:72-9
Monteggia, Lisa M (2016) Toward Better Animal Models for Molecular Psychiatry. Biol Psychiatry 79:2-3
Kavalali, Ege T; Monteggia, Lisa M (2015) How does ketamine elicit a rapid antidepressant response? Curr Opin Pharmacol 20:35-9
Monteggia, Lisa M; Zarate Jr, Carlos (2015) Antidepressant actions of ketamine: from molecular mechanisms to clinical practice. Curr Opin Neurobiol 30:139-43

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