The extracellular signal-regulated kinase pathway may play an important role in mediating antidepressant-stimulated hippocampus neurogenesis in depression
Introduction
Depression is a disorder characterized by a broad range of symptoms, including altered mood and cognitive functions, and also a severe mental health problem across the globe, with a lifetime risk of 10ā30% for women and 7ā15% for men [1]. It is one of the leading causes of disability burden in the world. Despite the devastating impact of depression, little is known about its etiology or pathophysiology. One of the reasons is due to the difficulty posed in evaluating pathological changes within the human brain. The pathogenesis of depression includes monoamine hypothesis, abnormal activity of the HPA axis hypothesis, neurotrophic signaling hypothesis, deficits in the brain reward processing and abnormal cognitive functioning. The monoaminergic hypothesis is the most popular one due to the fact that most antidepressants act on modulation of serotonin and norepinephrine neurotransmitter systems.
Over the past 60Ā years, antidepressants have developed from tricyclic antidepressants and monoamine oxidase inhibitors to selective serotonin reuptake inhibitors (SSRI), which is now the first-line therapy now. This is not because of their greater efficacy but rather due to their enhanced safety profile and reduced side effects. However, after antidepressants treatment, only about 60% of patients with depression can be cured. Moreover, antidepressants take 2ā4Ā weeks before they are effective. The immediate effects of antidepressants on serotonin and norepinephrine systems cannot explain the lag period of treatment effects. So the delayed therapeutic effect of antidepressant drugs may be due to neural plasticity which is in line with the time course of antidepressants. Animal model study suggests that hippocampal neurogenesis appears to be necessary for antidepressant drugs to alleviate depression-related behavioral changes. Therefore, it would be meaningful to identify changes in the intracellular signaling cascades that regulate cellular plasticity underlying delayed therapeutic efficacy of antidepressant drugs, which may be involved in antidepressants induced behavioral alterations.
The extracellular signal-regulated kinase (ERK) (include ERK1 and ERK2) pathway belongs to the mitogen-activated protein kinases (MAPKs) family [2]. ERK1/2 is activated by neurotrophins binding to the receptor tyrosine kinase (Trk) via activation of Ras-Raf-MEK-ERK cascade. Neurotrophins such as nerve growth factor (NGF), brain-derived nerve growth factor (BDNF), and NT-3/4 can trigger the pathway cascade. Phosphorylated ERK translocates from the cytosol to the nucleus, where it activates ribosomal protein S6 kinase-1 (RSK) [3] and the RSK-related mitogen- and stress-activated kinases (MSKs) by phosphorylation [4]. In the nucleus, ERKs, RSKs and MSKs phosphorylate transcription factor substrates, (cAMP response element binding (CREB), AP-1) or regulate cytoskeletal proteins, regulatory enzymes and other kinases directly. ERK pathway is activated by neurotrophins and other neuroactive chemicals and is involved in the differentiation, survival, apoptosis, structural and functional plasticity of neurons [5], [6] and also in learning and memory [7]. Recently, the role of the ERK pathway in depression has got more attention. It has been proved that expression of CREB and BDNF is decreased in stress animal models, and could be upregulated by chronic treatment with antidepressant and mood stabilizers. Enhanced cortical and hippocampal phosphorylated CREB (pCREB) has been proposed as a common antidepressants mechanism. It is well recognized that the two proteins play key roles in the survival and guidance of neurons during development, BDNF is especially required for the survival and normal functioning of neurons in the adult brain. These data indicate that the ERK pathway play an important role in neurogenesis. However, whether the ERK pathway takes part in antidepressant-increased neurogenesis in depression is still unclear.
Section snippets
The hypothesis
Based upon the findings from above mentioned studies, it is hypothesized that activation of the extracellular signal-regulated kinase pathway plays a role in progenitor cell proliferation in hippocampal SGZ after chronic antidepressants treatment.
Hippocampus neurogenesis in depression
Neurogenesis in the adult mammalian central nervous system occurs throughout lifespan. In mammalian brain, adult neurogenesis occurs in two important regions of the brain: the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles. The stages of adult neurogenesis include proliferation and lineage differentiation of neural stem cells (NSCs), migration of neuroblasts and integration of newborn neurons. NSCs refer to cells which can
Conclusion
The results above demonstrate the role of ERK signaling pathway in the molecular pathophysiology of antidepressants and in regulating neurogenesis. It seems reasonable to propose that the ERK signaling pathway participates in the increased neurogenesis in depression after antidepressant treatment. If validated, the hypothesis would allow us not only to better understand the mechanism by which antidepressants alleviate depression-like behavior, but also the histology and molecular mechanism of
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by the Science and Technology Commission of Shanghai Municipality (114119a5500, 09ZR1427200), and partly supported by Shanghai Jiao Tong University Grant (11XJ21006), National Natural Science Foundation of China (30971047), National High-tech R&D Program (863 Program, 2006AA02Z430, Ministry of Science and Technology of China).
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2020, Brain Research BulletinCitation Excerpt :This results in the augmentation of BDNF in the nervous system (Tiraboschi et al., 2004; Qi et al., 2008; Freitas et al., 2013). Other studies revealed that fluoxetine can increase the proliferation of neurons and promote neurogenesis in the CNS (Wang et al., 2012; Zavvari et al., 2020). Fluoxetine also increases the energy metabolism of neurons by accelerating glycogenolysis in the CNS (Kong et al., 2002).
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2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :This strongly supports the view that gene dosage impacting on the ERK pathway contributes to phenotype of the 16p11.2 CNV and that compounds targeting the ERK pathway may represent an effective therapeutic intervention. Finally, elevated ERK activity has been reported for the Fragile X mouse mutant, the Fmr1 KO (Wang et al., 2012), and the Ras-ERK inhibitor lovastatin has been shown to improve behavior in children and adults with FXS (Caku et al., 2014). It is thus possible to envision that pharmacological treatment with a Ras-ERK inhibitor may be useful for amelioration of attention and working memory deficits, and a rescue of the molecular and cellular phenotypes, in a number of developmental disorders with disparate etiology.
Negative affect predicts social functioning across schizophrenia and bipolar disorder: Findings from an integrated data analysis
2016, Psychiatry ResearchCitation Excerpt :If stress sensitivity is a precipitant of heightened negative affect in SZ and BD, as supported by findings mentioned previously (Alloy et al., 2006; Collip et al., 2013; Corcoran et al., 2012; Fries et al., 2014; Steen et al., 2014, 2011; Zimmerman et al., 2013), it is possible that antidepressants may ameliorate stress reactivity via physiological mechanisms that reduce HPA dysfunction (Jacobson, 2014), which may consequently reduce negative affect. For instance, antidepressants may promote hippocampal neurogenesis, which could improve stress response via modulation of HPA axis function (Surget et al., 2011; Wang et al., 2012). More generally, it may be the case that just as antidepressants reduce negative affect in depression, they also reduce negative affect in psychosis and bipolar disorder.
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2015, Pharmacology Biochemistry and BehaviorCitation Excerpt :U0126 suppress the activation of ERK1/2. There is some evidence that the ERK pathway might play a significant role in mediating antidepressant-stimulated hippocampal neurogenesis in depression (Duman et al., 2007; Wang et al., 2012). One study reported that the activation and expression of ERK1/2 MAP kinase is reduced in the post-mortem brains of depressed suicide subjects (Dwivedi et al., 2001).
ERK1/2: Function, signaling and implication in pain and pain-related anxio-depressive disorders
2015, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Indeed, it was already shown that neuropathic conditions were accompanied by hippocampal reduction of ERK1/2 activation, decreased neurogenesis as well as altered synaptic plasticity (Mutso et al., 2012). In parallel, taking as an example the use of antidepressants for the treatment of chronic pain (Verdu et al., 2008), it has already been shown that these drugs are able to increase neurogenesis in the hippocampus and that ERK1/2 may play a role on it (Wang et al., 2012). Throughout this literature review it is clear that ERK1/2 activation is quite an interesting target in pain and pain-related aspects.