Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy

Hauger, Richard L.; Olivares-Reyes, J. Alberto; Dautzenberg, Frank M.; Lohr, James B.; Braun, Sandra; Oakley, Robert H.

doi:10.1016/j.neuropharm.2011.11.007

Cited by 65 publications

(55 citation statements)

References 78 publications

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“…Several studies even suggest that activation of GSK3 could be an outcome of some susceptibility genes for mental disorders. A similar observation can be made for the potential contribution of AKT to the etiology of mental disorders [10]. Thus, regulation of AKT and GSK3 may constitute an important signaling center in the integration of monoamine neurotransmissions.…”

Section: Introductionsupporting

confidence: 59%

Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses

Kitagishi

Kobayashi

Kikuta

et al. 2012

Depression Research and Treatment

120

106

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Several pharmacological agents acting on monoamine neurotransmission are used for the management of mental illnesses. Regulation of PI3K/AKT and GSK3 pathways may constitute an important signaling center in the subcellular integration of the synaptic neurotransmission. The pathways also modulate neuronal cell proliferation, migration, and plasticity. There are evidences to suggest that inflammation of neuron contributes to the pathology of depression. Inflammatory activation of neuron contributes to the loss of glial elements, which are consistent with pathological findings characterizing the depression. A mechanism of anti-inflammatory reactions from antidepressant medications has been found to be associated with an enhancement of heme oxygenase-1 expression. This induction in brain is also important in neuroprotection and neuroplasticity. As enzymes involved in cell survival and neuroplasticity are relevant to neurotrophic factor dysregulation, the PI3K/AKT/GSK3 may provide an important signaling for the neuroprotection in depression. In this paper, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells in mental illnesses.

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Section: Introductionsupporting

confidence: 59%

Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses

Kitagishi

Kobayashi

Kikuta

et al. 2012

Depression Research and Treatment

120

106

View full text Add to dashboard Cite

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“…Of the subset that we validated, Fkbp5 is a known target of GR involved in negative regulation of GR and the stress response. Improper activity of Fkbp5 can contribute to neuropsychiatric diseases such as posttraumatic stress disorder (41). Alterations in the regulation of Fkbp5 may explain why adult Cav-1 KO animals tend to exhibit more anxious behaviors than their wild-type counterparts (42).…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

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“…Over time and with continuous exposure to stressors, both HPA and immune function become dysregulated. Although extensive work has been done to characterize the role of endocrine dysfunction in the pathophysiology and maintenance of PTSD (Daskalakis et al, 2013;Hauger et al, 2012;O'Donovan et al, 2013;Yehuda and LeDoux, 2007), our understanding of the role of inflammation in the etiology and maintenance of fear-and anxiety-based disorders remains limited. Thus, in the current review, we will summarize significant findings that indicate that PTSD, and other fear-and anxiety-based disorders, are characterized by increased inflammatory processes associated with greater symptom severity.…”

Section: Introductionmentioning

confidence: 99%

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

Michopoulos

Powers

Gillespie

et al. 2016

Neuropsychopharmacol

486

376

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The study of inflammation in fear-and anxiety-based disorders has gained interest as growing literature indicates that proinflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear-and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear-and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.

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Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy

Cited by 65 publications

References 78 publications

Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses

Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

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