We and several other investigators have previously reported that neurotransmitter receptors, such as serotonergic and adrenergic, and specific effectors of these receptor-mediated signal transduction systems are altered in the postmortem brain of suicide victims. Recent investigations in our laboratory have revealed that the functional characteristics and the expression of transcription factor CREB, a common substrate for many neurotransmitter receptor systems implicated in the pathophysiology of suicide, and the expressions of its target gene BDNF and receptor for BDNF, i.e., TrkB, are significantly altered in the postmortem brain of suicide victims, suggesting that these molecules may be playing an important role in the pathophysiology of suicidal behavior. However, the significance and consequences of these alterations at the functional level in suicide brain are not clear. ERK-1/2 and PI3-kinase cascades are the two most important signaling systems in the CNS that are activated by TrkB and mediate the physiological functions of BDNF. The major objective of the proposed research is to elucidate the cellular and the molecular mechanisms associated with suicide by examining whether abnormalities in BDNF and TrkB are associated with abnormalities further downstream in the ERK-1/2 and the PI3-kinase pathways, both at the level of kinases and at the functional level in the substrate molecules responsible for physiological actions in the brain. More specifically, in postmortem brain of suicide victims and well-matched nonpsychiatric control subjects, we will study the activation and the expression of upstream kinases Raf-1, MEK-1, ERK-1, ERK-2, PI3-kinase, Akt-1, Akt-3, and of downstream substrates, transcription factors Elk-1 and FKHRL1, and regulatory proteins Bcl-2 and Bad, both at the molecular and the cellular level. These studies will be performed in prefrontal cortical and hippocampal brain areas utilizing quantitative RT-PCR, Western blot, immunoprecipitation, enzymatic assays, in-situ hybridization, and gold-immunolabeling techniques. Furthermore, to examine whether observed changes are restricted to depression, we will compare the findings in the proposed measures between suicide victims with a firm diagnosis of major depression and those diagnosed with other psychiatric disorders. We will also study whether there is coordinated regulation of the proposed measures (upstream kinases, downstream substrates, and regulatory proteins) of the two signaling pathways within the same brain by examining the correlational structure overall and individually within the group and by statistical path analysis. The proposed research is based on the central hypothesis that there may be abnormalities in the components of ERK-1/2 and PI-3 kinase signaling pathways in postmortem brain of suicide victims, which may be associated with abnormalities in activation and/or expression of the substrate molecules responsible for BDNF-elicited neuronal functions, and that these abnormalities may play an important role in the pathophysiology of suicidal behavior. Elucidation of the alterations in ERK-1/2 and PI3-kinase pathways in postmortem brain of suicide victims will yield important information on the neurobiology of suicide and will indicate possible novel sites for therapeutic interventions, which may eventually lead to better treatment and possibly prevention of suicidal behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068777-03
Application #
7012304
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2004-04-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$239,727
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Dwivedi, Yogesh; Pandey, Ghanshyam N (2011) Elucidating biological risk factors in suicide: role of protein kinase A. Prog Neuropsychopharmacol Biol Psychiatry 35:831-41
Smalheiser, Neil R; Lugli, Giovanni; Rizavi, Hooriyah S et al. (2011) MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. Int J Neuropsychopharmacol 14:1315-25
Dwivedi, Yogesh (2010) Brain-derived neurotrophic factor and suicide pathogenesis. Ann Med 42:87-96
Dwivedi, Yogesh; Rizavi, Hooriyah S; Zhang, Hui et al. (2010) Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositide-dependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subject Biol Psychiatry 67:1017-25
Dwivedi, Yogesh; Rizavi, Hooriyah S; Zhang, Hui et al. (2009) Aberrant extracellular signal-regulated kinase (ERK)1/2 signalling in suicide brain: role of ERK kinase 1 (MEK1). Int J Neuropsychopharmacol 12:1337-54
Pandey, Ghanshyam N; Dwivedi, Yogesh; Rizavi, Hooriyah S et al. (2009) GSK-3beta gene expression in human postmortem brain: regional distribution, effects of age and suicide. Neurochem Res 34:274-85
Dwivedi, Yogesh; Rizavi, Hooriyah S; Zhang, Hui et al. (2009) Neurotrophin receptor activation and expression in human postmortem brain: effect of suicide. Biol Psychiatry 65:319-28
Pandey, Ghanshyam N; Ren, Xinguo; Rizavi, Hooriyah S et al. (2008) Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. Int J Neuropsychopharmacol 11:1047-61
Donati, Robert J; Dwivedi, Yogesh; Roberts, Rosalinda C et al. (2008) Postmortem brain tissue of depressed suicides reveals increased Gs alpha localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci 28:3042-50
Pandey, Ghanshyam N; Dwivedi, Yogesh; Ren, Xinguo et al. (2007) Cyclic AMP response element-binding protein in post-mortem brain of teenage suicide victims: specific decrease in the prefrontal cortex but not the hippocampus. Int J Neuropsychopharmacol 10:621-9

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