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Undergraduate Biological Sciences Journal (2015) A Brief Overview of Molecular Mechanisms of Depression and its Treatments Iya Prytkova1 and Dylan Barnes2 1 Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019 2 Department of Biology, University of Oklahoma, Norman, OK 73019 Contact information. Author: [email protected]. Corresponding author: [email protected]. INTRODUCTION Major depressive disorder (MDD) is a widespread, chronic, and debilitating mood disorder with a lifetime prevalence of up to 20% in the US adult population (Kessler et al., 2003). Its symptoms include loss of motivation, deleterious changes in sleep and appetite, anhedonia, feelings of despair, and suicidal thoughts. MDD may have lethal consequences such as suicide and cardiovascular disease (Bernard et al., 2011). This disorder, historically treated by exorcisms, lobotomies, and electroshock therapies (Nemade, Staats Reiss, & Dombeck, 2015), involves changes in brain chemistry. Biomolecules such as serotonin and norepinephrine have been implicated in its etiology (Papakostas & Ionescu, 2015). Despite the known molecular underpinnings, MDD is still very poorly understood and its mechanisms remain elusive. Current treatments which target noradrenergic neurotransmission produce remission in only 37% of all patients and in most cases take several weeks to come into effect (Bernard et al., 2011). Moreover, many experience severe side effects including nausea, loss of appetite, decrease in libido, fatigue, insomnia, dizziness, and increased anxiety (Ferguson, 2001). Although the exact etiology of depression is unclear, environmental and oxidative stress, epigenetics, and genetics have been shown to contribute to the diathesis of depression. Recent findings suggest the involvement of neuroendocrine, immuno-inflammatory, and metabolic pathways, revealing that depression may be a much more fundamental disturbance in physical function than previously assumed. This paper focuses on some of the current research on the molecular and cellular mechanisms underlying depression and the action of its treatments. ETIOLOGY unable to react normally and thus its ability to Oxidative Stress adapt is compromised. It has been shown that in The central nervous system (CNS) is crisis situations the dopaminergic reward system capable of quickly adapting to normal or severe increases its activity to maintain mental stability stressors. Under MDD conditions the brain is and well-being. However, stress mediators 2 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) downregulate this system, resulting in depressive Shortened telomeres can serve as a biomarker moods (Phillip W. Gold, Machado-Vieira, & for acceleration of cells aging due to exposure to Pavlatou, 2015; P. W. Gold & Chrousos, 2002). said stressors. Although the exact mechanisms Additionally, environmental stress has been of telomere shortening are unknown, oxidative shown to affect hippocampal neurogenesis, stress resulting from inflammation or stress glucocorticoid release, and the function of 5-HT hormones has been implicated. Reactive oxygen (serotonin) Bambico, species (ROS) produced by the brain, usually Mechawar, & Nobrega, 2014; Lupien, McEwen, mediators of the intracellular stress responses, Gunnar, & Heim, 2009), all of which have been with age play an increased role in cellular associated with the molecular and cellular damage. ROS react with DNA, among other mechanisms of depression. biological targets, attacking guanine nucleotides receptors (Mahar, Several links between stress and genetics in the pathology of depression have been made, including polymorphisms in glucocorticoid receptor-coding genes in mice (El Hage, Powell, & Surguladze, 2009; Mahar et al., 2014). Animals subjected to chronic unpredictable mild stress, a common animal model of depression (Czéh, Fuchs, Wiborg, & Simon, 2015), have increased glucocorticoid levels and decreased expression of hippocampal genes linked to synapse formation (Mahar et al., 2014). Similar effects were also observed in human patients (Brown, Varghese, & McEwen, 2004; Christiansen, Bouzinova, Palme, & Wiborg, 2012; Duric et al., 2013; Goldstein et al., 2000; Henningsen et al., 2012; Mahar et al., 2014). Stressors glucocorticoids, Because the especially telomere guanine region rich, of oxidative DNA is stress contributes to its shortening (Szebeni et al., 2014). Epigenetics Stress is widely accepted as a causal factor in depression and has been shown to induce changes in gene expression through mechanisms acetylation such of as DNA the methylation (Dalton, Kolshus, or & McLoughlin, 2014), (Heim & Binder, 2012). However, there is still an absence of predictors for anti-depressant response in patients, and effective treatments for each individual have to be determined via trial and error. It has been such and which are especially sensitive to oxidation. as that there are several distinct molecular mechanisms of MDD, depending on of whether the disorder is “endogenous,” meaning it increasing has no identifiable external cause, or “reactive,” likelihood of apoptosis or senescence observed meaning it is in response to a specific stressor. contribute telomeres in to the mononuclear stress suggested also frequently metabolic inflammation, shortening cells, in MDD (Blackburn, 2000; Szebeni et al., 2014). 3 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) Moreover, the timing of the stressor, distal or Ywhaz (tyrosine 3-monooxygenase/tryptophan 5- proximal, has also been shown to have an effect monooxygenase activation protein) is associated on antidepressant responses in patients (Malki et with neurogenesis and cell proliferation, which is al., 2014). consistent with the neurogenesis hypothesis for Using hippocampal tissues from three animal models for “reactive,” “endogenousdistal,” and “endogenous-proximal” depression, Malki et al. (2014) identified unique sets of genes involved in each animal model of depression in addition to a small group of genes that were involved in all three models. The gene network associated with the early (distal) stressors is primarily related to neurodevelopmental disorders, and the gene network associated with the late (proximal) stressors is involved in cell signaling and stress response. Moreover, the overlap in altered gene expression between the two reactive models was much smaller than that between either early or late stress and endogenous (9%, 19%, and 11%, respectively). This points to the existence of several significantly different mechanisms of depression which could account for the heterogeneity in responses to treatment (Malki et al., 2014). A small group of genes was also identified MDD. Nfkb plays a role in peripheral inflammation, which is in agreement with the inflammation theory of depression. Thus, despite the varying etiological stressors and their effects, there seems to be a commonality which could serve as a heterogeneity drug in target to eliminate antidepressant the responses among MDD patients (Malki et al., 2014). Genetics To date, MDD does not have any single causative risk factor and is hypothesized to be a composite polygenic phenotype (Sarosi et al., 2008). Single nucleotide polymorphisms (SNPs) play an important role in the etiology of depression, but genome-wide association studies (GWAS) have failed to determine significant genome-wide associations between MDD and SNPs (Lubke et al., 2012; Sullivan et al., 2009; Wray et al., 2012). However, alternative methods focusing on the additive effects of SNPs and phenotypic variance determined that SNPs that was differentially regulated across the three explain a significant fraction of the heritability of models, which could represent a common MDD phenotype and the variance in treatment pathway to major depressive disorder. Identified responses (Lubke et al., 2012). genes include Ppm1a, Ywhaz, Nfkb, and Mapk. Ppm1a expression has been shown to be significantly altered by nortiptyline (a tricyclic antidepressant), and the human analog of the gene exhibited similar responses to the drug. The most prominent SNP site associated with the therapeutic response to selective serotonin reuptake inhibitors (SSRIs) in MDD patients occurs in the transcriptional control 4 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) region of the serotonin transporter gene (Tsai et downregulation of ASMT has been linked to al., 2009). Sarosi et al. (2008) investigated the cognitive impairment (Gałecki, 2014). Thus, it STin2 seems that melatonin misregulation is consistent (serotonin transporter intron 2) polymorphism, which has been hypothesized to with the neuroplasticity, inflammation, have an effect on the serotonin transporter metabolic theories of depression. and expression levels. The researchers found that the presence of one or two copies of the KEY PLAYERS IN THE MECHANISMS OF STin2.10 allele was linked to suicide completion DEPRESSION and Locus coeruleus cognitive impairment in MDD. This polymorphism affected attention, verbal learning and memory, but it did not affect executive function and visual memory. Individuals with the STin2.12 allele, which is linked to higher expression levels of the serotonin transporter, performed significantly better than STin2.10 carriers on cognitive assessment tests. Moreover STin2.10/STin2.12 genotype has been shown to be less responsive to SSRI treatments than the STin2.12/STin2.12 genotype (Sarosi et al., 2008). In the mammalian brain, locus coeruleus (LC) has the highest levels of norepinephrine (NE)-producing neurons, which project throughout the entire CNS. Among many other areas, the LC is connected with the hippocampus, hypothalamus, thalamus, cerebral cortex, and 5-HT-producing raphe neurons. Together, the LC and raphe neurons regulate serotonergic and noradrenergic systems and modulate circadian rhythms, memory, and responses to stress (Bernard et al., 2011; One more SNP affected gene related to Loughlin, Foote, & Bloom, 1986; Loughlin, Foote, cognitive impairment is AMST (N-acetylserotonin & Fallon, 1982). Because all of these systems O-methyltransferase), which has been shown to and functions have been implicated in the be downregulated in MDD patients. ASMT etiology of depression, the LC is an attractive catalyzes the conversion of N-acetylserotonin to research target. melatonin and is the limiting enzyme in melatonin formation (Sugden, Ceña, & Klein, 1987), (Reiter, Tan, Terron, Flores, & Czarnocki, 2007). Melatonin is involved in sleep induction, circadian rhythms, memory, metabolic regulation, antioxidative defense, and memory (Pagan et al., 2011). Because melatonin is involved in neuroplasticity and enhances cell survival, the Several proteins that play a role in the disturbances of NE production levels in the LC have been identified. Postmortem studies in MDD patients expression of have revealed presynaptic increased alpha 2 adrenoreceptors, which inhibit firing of neurons and NE secretion. Additionally, tyrosine hydroxylase (a rate limiting enzyme in NE 5 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) synthesis) is upregulated. Expression of 2011). Glial cells also play a significant role in glutamate signaling genes was also altered pathology of bipolar disorder (Dong & Zhen, (Bernard et al., 2011). 2015). Beneddeto et al. postulated that glial cells Because the LC locally expresses mRNA subunits for several different metabotropic glutamine receptors (GRM) and subunits for alpha-amino-3-hydroxyl-5-methyl-4-isoxazole (AMPA) receptors, which elicit norepinephrine release, it has been postulated that glutamate drives norepinephrine turnover in the LC. Bernard et. al (2011) found that the glutamate signaling pathway was the most significantly altered in the LC of MDD patients. Moreover, only glial cells exhibited expression changes of glutamate signaling genes including may serve as substrates for antidepressants’ restructuring of the neuronal network, which is mis-wired as a result of MDD (Di Benedetto, Rupprecht, & Czéh, 2013). Additionally, glia have been shown to respond to non-pharmacological therapies in animal models of depression, such as chronic electroconvulsive shock, which has been shown to increase CNS glial cell proliferation in the hippocampus, piriform cortex, and prefrontal cortex (Rajkowska & Stockmeier, 2013). the The reduction of glial cells, particularly downregulation of a high affinity glutamate astrocytes, in the postmortem prefrontal cortex transporter (SLC1A3). SLC1A3 mediates glial (PFC) has been widely reported in subjects with glutamate reuptake and maintains synaptic MDD. Histological analyses of MDD anterior glutamate concentrations to protect neurons from cingulate cortex white matter have also revealed excitotoxicity. The expression of GLUL, an a hypertrophy (i.e. inflammation) of astrocytic enzyme that converts glutamate to glutamine, processes and cell bodies, supporting the theory was also decreased in the MDD locus coeruleus, of the involvement of neuro-inflammatory system inferior frontal gyrus, anterior cingulated and in depression (Rajkowska & Stockmeier, 2013). dorsolateral prefrontal cortex (Bernard et al., Among numerous other functions, astrocytes 2011). mediate the connection between vasculature and neuronal tissue through projections dubbed Glia “endfeet”. Astrocytic endfeet are also a major Glial cells regulate neurotransmitter component of the blood brain barrier (BBB), density and reuptake, and have been shown to which is frequently impaired in MDD. AQP4 (a be involved in the molecular mechanisms of protein mainly expressed in astrocytic endfeet) depression. Postmortem studies have found a helps decrease in glial cell number and density in MDD distribution and ion transportation. Rajkowska et cortical and limbic brain regions (Bernard et al., al. (2013) used immunofluorescent techniques to maintain the BBB through water 6 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) track the presence of AQP4 in the PFC and presence of S100B (a calcium binding protein found that only the orbitofrontal gray matter produced by astrocytes) in cerebrospinal fluid expressed a significant reduction in AQP4 as a during result of MDD. A decrease in the number of Oligodendrocytes, too, have been shown to play endfeet could reduce the overall exchange of a role in the mechanisms of MDD due to the nutrients significant with the circulatory system, thus major depressive shortening of episodes. oligodendrocyte implicating the circulatory system as yet another telomere lengths compared with astrocytes, component neurons, and other brain cells in MDD patients of MDD pathology (Rajkowska, Hughes, Stockmeier, Miguel-Hidalgo, & Maciag, (Szebeni et al., 2014). 2013). The role of astrocytes in glutamate neurotransmission has also been extensively studied in MDD pathology. It has been determined that glutamate transporters and glutamine synthetase are disregulated in postmortem MDD brain tissue, specifically in the anterior cingulate, dorsolateral prefrontal cortex, premotor cortex, locus coeruleus, and the amygdala (Rajkowska & Stockmeier, 2013), (Bernard et al., 2011). The degeneration of astrocytes as a result of depression results in glutamate/GABA imbalance in the affected structures in addition to an excess of glutamate in the synaptic cleft (Śmialowska, Szewczyk, Woźniak, Wawrzak-Wlecia, & Domin, 2013), thus leading to excitotoxicity. Together, these findings suggest a global dysfunction in astrocytemediated glutamate signaling in MDD. Hippocampus The hippocampus is one of the few brain areas that facilitates adult neurogenesis, and disruption of that process has been implicated in many mental disorders, including Alzheimer’s, bipolar disorder, post-traumatic stress disorder, and major depressive disorder (Ge et al., 2015). It is involved in learning, memory, motivational control, and emotional control, and it connects to the PFC, thalamus, basal ganglia, hypothalamus, and amygdala, which form the mood regulation network. Hippocampal reduction in volume has also been well-documented in MDD patients (Cao et al., 2012), and it has been shown that greater severity of hippocampal size reduction corresponds with poorer responses to treatments (Lai, 2014). The hippocampus also mediates the hypothalamic-pituitary-adrenal (HPA) axis and expresses a high number of 5-HT and Glial cells also have been implicated in GABAergic receptors (Ge et al., 2015), making it depression in a number of other ways, including a popular therapeutic target for antidepressant abnormal morphology and function of astrocytic action. gap junctions in MDD brains, upregulation of connexin proteins in response to SSRIs, and the 7 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) Antidepressant been dysregulation of HPA axis function in MDD. shown to stimulate the proliferation of neural Medina et. al (2013) demonstrated significantly progenitor different cells treatments in the have dentate gyrus (a levels of MR expression in the substructure of the hippocampal formation). hippocampus. Interestingly, they found that MR Moreover, anti-depressive anti-anxiety expression decreased in the anterior but not effects fluoxetine used anti- posterior hippocampus of MDD patients while GR depressant also known as Prozac) have been expression remained unaltered. The researchers shown to fail in the absence of hippocampal hypothesized that normal HPA axis function neurogenesis (David et al., 2009). The stunted depends on a delicate balance between MR and neurogenesis and hippocampal cell apoptosis GR receptors and their relative abundance in associated with depression therefore suggest different hippocampal regions. The imbalance that long term depression may be more resistant between the two likely contributes to stress- to related dysfunction in MDD. of SSRI treatment. (a and widely Patients with chronic depression not only exhibit higher symptom severity, but also lower remission rates in Neuro-inflammatory pathways response to treatment. However, the phenomena Numerous studies have demonstrated that was not in any way affected by differences in major pharmacological treatments, suggesting that, inflammatory even if the stunted neurogenesis hypothesis of proinflammatory long term depression is true, there are other secreted by immune system cells that play a role factors at play (Köhler et al., 2015). in cell communication) have been found in The importance of the hippocampus in the etiology of depression also stems from its susceptibility to stressors. The HPA axis controls mammalian stress response by controlling glucocorticoid production, and its hyperactivity has been linked to MDD and other mood disorders (Medina et al., 2013). In the hippocampus, glucocorticoids, mediated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), play a role in plasticity and neuronal excitability. MR and GR have been hypothesized to affect the depressive disorder disease. is Increased cytokines (small also an levels of proteins patients with symptoms of depression and neurodegeneration. Several hypotheses exist about the role cytokines play in MDD pathogenesis. One theory is that cytokines stimulate the conversion of tryptophan to kynurenine by indoleamine 2, 3-dioxygenase (IDO) in glial cells (Miller, Haroon, Raison, & Felger, 2013; Noto et al., 2014). Kynurenine may then be transformed into quinolinic acid, which binds to NMDA receptors and depletes tryptophan (a precursor of serotonin). This leads to an increase in glutamatergic activity and 8 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) neurotoxicity that is likely responsible for the demonstrated neuronal cell death and loss of plasticity responsive characteristic in MDD. accelerated response after a course of aspirin. Among the proinflammatory cytokines believed to be at the top of the stress-induced inflammatory cascade is the proinflammatory cytokine interleukin-1 beta (IL-1β), which has been shown to be involved in inflammatory responses leading damage to stress-related (Gądek-Michalska, cellular Tadeusz, Rachwalska, & Bugajski, 2013; Pan, Chen, Zhang, & Kong, 2014). IL-1β expression is significantly upregulated in MDD PFCs in both rats and humans, and antidepressants block its inflammatory effects (Pandey et al., 2012; Pan et al., 2014; You et al., 2011). NLRP3 inflammasome (nucleotide binding receptor) is involved in IL-1β synthesis and regulates transcription and function of IL-1β in the nuclear factor kappa B inflammatory pathway, which regulates proinflammatory cytokine production and cell survival (Lawrence, 2009; Pan et al., 2014). NLRP3 inflammasome and its associated proteins are also over-expressed in MDD that to patients SSRI who treatments are non- exhibit an Celecoxib has been shown to have antidepressive effects on its own and to be very effective in combination with fluoxetine in decreasing depressive symptoms (Noto et al., 2014). TREATMENTS Traditional typically treatments feature tricyclic for depression anti-depressants, selective serotonin reuptake inhibitors (SSRIs), and, more recently, selective norepinephrine reuptake inhibitors glutamatergic (SNRIs). Additionally, neurotransmission has been hypothesized to be involved in the therapeutic action of many antidepressant drugs, such as phenelzine (an irreversible non-selective inhibitor of monoamine oxidase) (DrugBank, 2013; Śmialowska et al., 2013). However, the exact mechanisms of action of these compounds are not very well understood and are current subject of intense research. patients with inflammation as well as in rats One of the current therapeutic research subjected to chronic unpredictable mild stress. targets are mood altering agents that promote Pan et al. (2014) demonstrated that IL-1β likely neuronal survival and alter energy levels. For plays a role in initiating the inflammatory cascade example, creatine is an ergogenic compound that in response to stress has been shown to possess anti-depressant Several anti-inflammatory agents have been investigated as treatments for MDD, including aspirin, celecoxib, and TNF-α (tumor necrosis factor) antagonists. One study action in treatment-resistant patients. The creatine-phosphocreatine system stores energy and controls its availability in tissues that have fluctuating energy needs, such as the brain, thus 9 I. Prytkova and D. Barnes/Undergraduate Biological Sciences Journal (2015) creating a metabolic barrier to prevent energy expressed proteins have been identified that exhaustion and cell death. Chronic administration were of creatine resulted in diametrically opposed communication pathways as well. However, effects in male and female rats, with male rats those proteins were either only altered by CMS more vulnerable to the negative effects of and unaffected by oleamide and vice versa, creatine. anti- making it difficult to establish links to the anti- depressant-like effects in female rats, which is depressive actions of oleamide (Ge et al., 2015). consistent with prior findings (Brotto, Barr, & Nonetheless, potential new therapeutic targets Gorzalka, 2000; Drossopoulou et al., 2004; have been identified. Conversely, creatine had involved in metabolic and cell Lifschytz, Shalom, Lerer, & Newman, 2006) that responses to antidepressant treatments are sex- CONCLUSIONS dependent (Allen, D’Anci, Kanarek, & Renshaw, Contrary to prior beliefs, depression is not 2010). This difference between sexes poses yet simply an emotional disorder, nor can it be solely another question about the mechanisms of explained by the decrease of serotonin levels. depression and demonstrates the difficulties in Major regulating the neural function. malfunction Another research target is oleamide, an endogenous bioactive lipid signaling molecule which has been shown to evoke anti-anxiety and anti-inflammatory effects. Oleamide (OLE) treatment of rats subject to chronic mild stress (CMS) proteins revealed that several were key hippocampal differentially expressed between the CMS and CMS + OLE groups. For example, GSTA4, a protein involved in oxidation pathways, was upregulated in the CMS group and downregulated following oleamide treatment. The increase in GSTA4 expression is likely part of a protective mechanism against oxidative damage. The fact that GSTA4 is downregulated following oleamide treatment suggests that oleamide reverses or hinders oxidative damage caused by CMS. Several other differentially depressive neurogenesis, disorder is affecting and a common inflammatory, neuroendocrine systems. Scientists have gained a deeper understanding of the etiology of depression through epigenetics and genetics and a deeper understanding of the cellular and molecular mechanisms underlying the disorder. Ultimately, the goal is to use this knowledge to develop treatments, or even preventative measures, for major depressive disorder. In addition to being a wide-spread mental disorder, MDD also has a high rate of comorbidity other afflictions, including panic disorder, alcoholism, addictions, cardiovascular disease, diabetes, dementia, and osteoporosis (Ferentinos et al., 2015; Lai, 2014; Szebeni et al., 2014; Wolkowitz, Reus, & Mellon, 2011). 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