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.
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.
|Dwivedi, Yogesh (2014) Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications. Dialogues Clin Neurosci 16:43-61|
|Dwivedi, Yogesh (2013) Involvement of brain-derived neurotrophic factor in late-life depression. Am J Geriatr Psychiatry 21:433-49|
|Smalheiser, Neil R; Lugli, Giovanni; Rizavi, Hooriyah S et al. (2012) MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One 7:e33201|
|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; Pandey, Ghanshyam N (2011) Elucidating biological risk factors in suicide: role of protein kinase A. Prog Neuropsychopharmacol Biol Psychiatry 35:831-41|
|Dwivedi, Yogesh (2011) Evidence demonstrating role of microRNAs in the etiopathology of major depression. J Chem Neuroanat 42:142-56|
|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 (2010) Brain-derived neurotrophic factor and suicide pathogenesis. Ann Med 42:87-96|
|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|