Antidepressants and Intracellular Signaling Linked to BDNF

Summary

Principal Investigator: Lisa Monteggia
Affiliation: University of Texas Southwestern Medical Center
Country: USA
Abstract: ABSTRACT 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.
Funding Period: ----------------2004 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. ncbi Reciprocal interaction of serotonin and neuronal activity in regulation of cAMP-responsive element-dependent gene expression
    Melissa A Mahgoub
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, 75390 9070, USA
    J Pharmacol Exp Ther 317:88-96. 2006
  2. doi Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor
    Madhurima Benekareddy
    Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
    Int J Neuropsychopharmacol 16:405-15. 2013
  3. doi Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice
    Teresa F Burke
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229 3900, USA
    Int J Neuropsychopharmacol 16:631-45. 2013
  4. pmc The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine
    Lisa M Monteggia
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Biol Psychiatry 73:1199-203. 2013
  5. ncbi Synaptic mechanisms underlying rapid antidepressant action of ketamine
    Ege T Kavalali
    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, USA
    Am J Psychiatry 169:1150-6. 2012
  6. pmc Acute suppression of spontaneous neurotransmission drives synaptic potentiation
    Elena Nosyreva
    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9111, USA
    J Neurosci 33:6990-7002. 2013
  7. pmc Epigenetics and psychiatry
    Melissa Mahgoub
    Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390 9111, USA
    Neurotherapeutics 10:734-41. 2013
  8. doi mTOR complexes in neurodevelopmental and neuropsychiatric disorders
    Mauro Costa-Mattioli
    Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
    Nat Neurosci 16:1537-43. 2013
  9. pmc Reelin mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission
    Manjot Bal
    Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
    Neuron 80:934-46. 2013
  10. pmc VGF, a new player in antidepressant action?
    Jessica E Malberg
    PsychoGenics, Inc, Tarrytown, NY 10591, USA
    Sci Signal 1:pe19. 2008

Scientific Experts

  • Lisa Monteggia
  • Anita E Autry
  • Ege T Kavalali
  • Megumi Adachi
  • Manjot Bal
  • Elena Nosyreva
  • Elisa S Na
  • Yildirim Sara
  • Julie G Hensler
  • Melissa Mahgoub
  • Madhurima Benekareddy
  • Mauro Costa-Mattioli
  • Teresa F Burke
  • Tushar Advani
  • Mohd W Akhtar
  • Jessica E Malberg
  • Jill B Becker
  • Melanie Lippmann
  • Melissa A Mahgoub
  • Alexey G Ryazanov
  • Denise M O Ramirez
  • Murat Durakoglugil
  • Austin L Reese
  • Deepika Suri
  • Brian G Dias
  • Amrita R Nair
  • Joachim Herz
  • Jeremy Leitz
  • Kristen Szabla
  • Vidita A Vaidya
  • Peng Fei Cheng
  • Maarten F Los
  • Pengfei Cheng
  • Rusty L Montgomery
  • Eric N Olson
  • Jesica Raingo
  • Erika D Nelson
  • Michel Barrot
  • David Theobald
  • Charles B Nemeroff
  • Rachel Yehuda
  • Jane R Taylor
  • Russell D Romeo
  • Aaron Bress
  • Paul M Plotsky
  • Tara S Perrot-Sinal
  • Tracy L Bale

Detail Information

Publications25

  1. ncbi Reciprocal interaction of serotonin and neuronal activity in regulation of cAMP-responsive element-dependent gene expression
    Melissa A Mahgoub
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, 75390 9070, USA
    J Pharmacol Exp Ther 317:88-96. 2006
    ..Taken together, these results suggest a reciprocal inhibitory interaction between neuronal activity and 5-HT in the regulation of cAMP response element-dependent gene expression in hippocampal neurons...
  2. doi Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor
    Madhurima Benekareddy
    Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
    Int J Neuropsychopharmacol 16:405-15. 2013
    ..These findings suggest the possibility that the regulation of Arc expression via BDNF provides a molecular substrate for the structural and synaptic plasticity observed following stimuli such as stress and hallucinogens...
  3. doi Sensitivity of hippocampal 5-HT1A receptors to mild stress in BDNF-deficient mice
    Teresa F Burke
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229 3900, USA
    Int J Neuropsychopharmacol 16:631-45. 2013
    ....
  4. pmc The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine
    Lisa M Monteggia
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Biol Psychiatry 73:1199-203. 2013
    ..This article outlines our recent studies on the synaptic mechanisms that underlie ketamine action, in particular the properties of eEF2K as a potential antidepressant target...
  5. ncbi Synaptic mechanisms underlying rapid antidepressant action of ketamine
    Ege T Kavalali
    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, USA
    Am J Psychiatry 169:1150-6. 2012
    ....
  6. pmc Acute suppression of spontaneous neurotransmission drives synaptic potentiation
    Elena Nosyreva
    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9111, USA
    J Neurosci 33:6990-7002. 2013
    ..These findings uncover an unexpectedly dynamic impact of spontaneous glutamate release on synaptic efficacy and provide new insight into a key synaptic substrate for rapid antidepressant action...
  7. pmc Epigenetics and psychiatry
    Melissa Mahgoub
    Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390 9111, USA
    Neurotherapeutics 10:734-41. 2013
    ..In this review we will discuss some of the latest work implicating a potential role for epigenetics in psychiatric disorders, namely, depression, addiction, and schizophrenia as well as a possible role in treatment. ..
  8. doi mTOR complexes in neurodevelopmental and neuropsychiatric disorders
    Mauro Costa-Mattioli
    Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA
    Nat Neurosci 16:1537-43. 2013
    ..In addition, we discuss the medical relevance of these findings. ..
  9. pmc Reelin mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission
    Manjot Bal
    Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
    Neuron 80:934-46. 2013
    ..These results uncover a presynaptic regulatory pathway that utilizes the heterogeneity of synaptic vesicle-associated SNAREs and selectively augments action potential-independent neurotransmission. ..
  10. pmc VGF, a new player in antidepressant action?
    Jessica E Malberg
    PsychoGenics, Inc, Tarrytown, NY 10591, USA
    Sci Signal 1:pe19. 2008
    ..These studies use in vivo approaches to link VGF to the antidepressant-like behavioral effects produced by antidepressant drugs and exercise...
  11. ncbi Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors
    Lisa M Monteggia
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390 9070, USA
    Biol Psychiatry 61:187-97. 2007
    ....
  12. ncbi Regulation of serotonin-1A receptor function in inducible brain-derived neurotrophic factor knockout mice after administration of corticosterone
    Julie G Hensler
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229 3900, USA
    Biol Psychiatry 62:521-9. 2007
    ....
  13. ncbi Long-term behavioural and molecular alterations associated with maternal separation in rats
    Melanie Lippmann
    Department of Psychiatry, The University of Texas South Western Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9070, USA
    Eur J Neurosci 25:3091-8. 2007
    ..Recognition of these adaptations begins to define the brain regions, and neural circuitry, associated with persistent alterations induced by early life stressors and the development of mood disorders...
  14. ncbi Stress and disease: is being female a predisposing factor?
    Jill B Becker
    Department of Psychology, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Neurosci 27:11851-5. 2007
  15. pmc Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy
    Megumi Adachi
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 9070, USA
    Biol Psychiatry 63:642-9. 2008
    ....
  16. ncbi Elucidating the role of brain-derived neurotrophic factor in the brain
    Lisa M Monteggia
    Department of Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9070, USA
    Am J Psychiatry 164:1790. 2007
  17. pmc Brain-derived neurotrophic factor and neuropsychiatric disorders
    Anita E Autry
    Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9070, USA
    Pharmacol Rev 64:238-58. 2012
    ..The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development...
  18. pmc Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior
    Anita E Autry
    Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 9070, USA
    Biol Psychiatry 66:84-90. 2009
    ..The neurotrophic hypothesis of depression suggests that loss of brain-derived neurotrophic factor (BDNF) may increase susceptibility for depression-like behavior, although direct evidence is lacking...
  19. pmc NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
    Anita E Autry
    Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390 9111, USA
    Nature 475:91-5. 2011
    ..Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants...
  20. pmc Use-dependent AMPA receptor block reveals segregation of spontaneous and evoked glutamatergic neurotransmission
    Yildirim Sara
    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9111, USA
    J Neurosci 31:5378-82. 2011
    ..These results support the notion that spontaneous and evoked neurotransmission activate distinct sets of AMPA receptors and bolster the hypothesis that synapses harbor separate microdomains of evoked and spontaneous signaling...
  21. pmc Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function
    Mohd W Akhtar
    Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9111, USA
    J Neurosci 29:8288-97. 2009
    ..Therefore, we propose that HDAC1 and HDAC2 form a developmental switch that controls synapse maturation and function acting in a manner dependent on the maturational states of neuronal networks...
  22. pmc The role of MeCP2 in CNS development and function
    Elisa S Na
    Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9070, USA
    Horm Behav 59:364-8. 2011
    ..This review will discuss the role of MeCP2 in CNS development and function, as well as a potential important role for MeCP2 and epigenetic processes involved in mediating transcriptional repression in Rett syndrome...