Brain-derived neurotrophic factor (BDNF) is the most prevalent neurotrophin in brain;via actions on its high affinity trkB receptor it enhances the survival of many types of central neurons and is implicated in several forms of neural plasticity in the brain. Recent work suggests that endogenous BDNF in the hippocampus may be involved in mediating antidepressant responses, in depression models in mice. A rather surprising finding in the field of depression has been the demonstration that ketamine, an ionotropic glutamatergic n-methyl-daspartate (NMDA) receptor antagonist, has rapid and long-lasting antidepressant effects in depressed individuals. We have started to investigate the mechanisms of the antidepressant activity of ketamine, specifically the potential involvement of endogenous BDNF in the hippocampus. In preliminary experiments, we find that the NMDA receptor antagonists, ketamine, MK801 or CPP, produce fast-acting antidepressant behavioral effects in depression models in mice. The fast acting antidepressant effects of ketamine occurs via a BDNF dependent manner because these effects are lost in forebrain specific BDNF knockout mice. Our findings also suggest that the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels 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. In agreement with recent in vitro work, we find that ketamine causes a decrease in phosphorylation of eukaryotic elongation factor 2 (eEF2), which normally impedes translation in its phosphorylated state, suggesting translational de-repression of BDNF mRNA. Importantly, we provide preliminary evidence that inhibitors of the eEF2 kinase (also called CaMKIII) that normally phosphorylates eEF2 trigger a fast-acting antidepressant-like effect in depression models in mice. These findings suggest a behavioral and clinically relevant correlate of dendritic translational de-repression by NMDA receptors. The objective of this grant is to link the regulation of translational repression to the effects of antidepressants. Collectively, these studies promise to provide fundamentally novel information concerning how endogenous BDNF in the hippocampus is involved in the fast acting antidepressant response of ketamine and offer new leads toward the development of faster acting antidepressants.

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. These studies will use molecular, cellular and behavioral approaches to investigate the the signaling pathways involved in mediating fast acting antidepressant responses, in the hopes of developing faster acting antidepressants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH070727-08
Application #
8260276
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (03))
Program Officer
Winsky, Lois M
Project Start
2004-04-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$393,112
Indirect Cost
$145,612
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
Kavalali, Ege T; Monteggia, Lisa M (2015) How does ketamine elicit a rapid antidepressant response? Curr Opin Pharmacol 20:35-9
Gideons, Erinn S; Kavalali, Ege T; Monteggia, Lisa M (2014) Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci U S A 111:8649-54
Burke, Teresa F; Advani, Tushar; Adachi, Megumi et al. (2013) Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice. Int J Neuropsychopharmacol 16:631-45
Mahgoub, Melissa; Monteggia, Lisa M (2013) Epigenetics and psychiatry. Neurotherapeutics 10:734-41
Monteggia, Lisa M; Gideons, Erinn; Kavalali, Ege T (2013) The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol Psychiatry 73:1199-203
Costa-Mattioli, Mauro; Monteggia, Lisa M (2013) mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 16:1537-43
Nosyreva, Elena; Szabla, Kristen; Autry, Anita E et al. (2013) Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci 33:6990-7002
Monteggia, Lisa M; Kavalali, Ege T (2013) Scopolamine and ketamine: evidence of convergence? Biol Psychiatry 74:712-3
Autry, Anita E; Monteggia, Lisa M (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238-58
Na, Elisa S; Monteggia, Lisa M (2011) The role of MeCP2 in CNS development and function. Horm Behav 59:364-8

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