Altered synaptic and structural plasticity play a crucial role in the pathogenesis of major depressive disorder (MDD);however, the precise molecular and cellular nature of events that lead to such altered plasticity remains unclear. Ca2+ is one of the critical molecules that play a decisive role in initiating and regulating synaptic and structural plasticity. A considerable body of evidence points to altered Ca2+ homeostasis and Ca2+ signaling in MDD. The varied effects of Ca2+ are mediated through Ca2+ sensing proteins;one highly characterized member is calmodulin (CaM). Recently, two different subfamilies of Ca2+ sensing proteins have been identified, i.e., neuronal Ca2+ sensing (NCS) and calcium binding (CaBP) proteins, that are solely or highly expressed in neurons. These proteins bind to Ca2+ with a very high affinity, undergo myristoylation and conformational changes, and thereby, interact with specific target proteins to mediate neuronal functions. These Ca2+ sensing/binding proteins and their novel target proteins have become a focus of great interest as potential molecular switches for plasticity phenomena. In a preliminary study, we found that the expression of Ca2+ sensing proteins are not only differentially regulated, but their interaction with specific target proteins are also disturbed in brains of MDD subjects. These changes were quite specific as either opposite or no changes were found in other mental disorders, i.e., bipolar disorder (BPD) or schizophrenia (SCHIZ). We hypothesize that Ca2+ sensing proteins, via their altered expression in a distinct manner, will affect their interactions with specific target proteins, which will lead to modulation in neural network/pathways, implicated in neural plasticity;these alterations will contribute to the pathogenesis of MDD. To test this, we propose a series of experiments examining Ca2+ sensing and their specific target proteins at molecular and cellular levels, in well-characterized and well-matched brain samples obtained from MDD and nonpsychiatric normal control subjects. We will examine the specificity of these changes by determining the proposed measures in brains of BPD or SCHIZ subjects. In addition, we will determine the consistency of changes in MDD by examining brain samples obtained from a different cohort. These studies will be performed in two brain areas, implicated in affective illnesses, namely, PFC and hippocampus. More specifically, we will examine: 1) expression and/or functional characteristics of a) NCS proteins NCS-1, VILIP1, VILIP2, VILIP3, hippocalcin, neurocalcin 4, and DREAM;b) CaBP proteins CaBP1 and CaBP4;and c) calmodulin;2) the interactions of these Ca2+ sensing proteins with specific targets, i.e., PI 4-kinase 2, inositol trisphosphate receptors, CREB, neuronal apoptotic inhibitory protein, CaM kinase II, CaM kinase IV, and calcineurin;3) the expression and/or functional characteristics of these target proteins. Our proposed study could lead to a fundamental breakthrough in our understanding of the molecular mechanisms associated with MDD, and also provide critical new insight for novel target-based drug discoveries for the treatment of MDD.

Public Health Relevance

Our proposed study will yield important information on the neurobiology of depression and may indicate possible novel sites for therapeutic interventions, which may eventually lead to better treatment and possibly prevention of depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082802-05
Application #
8449196
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Meinecke, Douglas L
Project Start
2009-08-01
Project End
2013-08-15
Budget Start
2013-04-01
Budget End
2013-08-15
Support Year
5
Fiscal Year
2013
Total Cost
$10,243
Indirect Cost
$3,647
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Dwivedi, Yogesh; Zhang, Hui (2016) Altered ERK1/2 Signaling in the Brain of Learned Helpless Rats: Relevance in Vulnerability to Developing Stress-Induced Depression. Neural Plast 2016:7383724
Ludwig, B; Dwivedi, Y (2016) Dissecting bipolar disorder complexity through epigenomic approach. Mol Psychiatry 21:1490-1498
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Amodeo, Dionisio A; Grospe, Gena; Zang, Hui et al. (2016) Cognitive flexibility impairment and reduced frontal cortex BDNF expression in the ouabain model of mania. Neuroscience :
Timberlake 2nd, Matthew A; Dwivedi, Yogesh (2015) Altered Expression of Endoplasmic Reticulum Stress Associated Genes in Hippocampus of Learned Helpless Rats: Relevance to Depression Pathophysiology. Front Pharmacol 6:319
Dwivedi, Y; Roy, B; Lugli, G et al. (2015) Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: relevance to depression pathophysiology. Transl Psychiatry 5:e682
Serafini, Gianluca; Hayley, Shawn; Pompili, Maurizio et al. (2014) Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets? CNS Neurol Disord Drug Targets 13:1708-21
Dwivedi, Yogesh (2014) Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications. Dialogues Clin Neurosci 16:43-61
Dwivedi, Yogesh (2013) microRNAs as Biomarker in Depression Pathogenesis. Ann Psychiatry Ment Health 1:1003

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