Pharmacological modulation of astrocytes and the role of cell type-specific histone modifications for the treatment of mood disorders

Jakovcevski, Mira; Akbarian, Schahram; Benedetto, Barbara Di

doi:10.1016/j.coph.2015.10.002

Cited by 9 publications

(4 citation statements)

References 40 publications

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“…Differential protein expression was more subtle in post-acute COVID participants with high uptake in other tissue ROIs (bone marrow, pharyngeal tonsils, gut wall, nasal turbinates) as in Supplemental Fig 6 , although there was some evidence for increased differential expression of gene products in post-acute COVID participants with high uptake in the spinal cord which, interestingly, included gene products associated with Alzheimer disease (AGER) 63 , myogenesis/myelination (Cdon 64 ), and oxidative stress and monocyte adhesion (MEGF10) protein also involved in mediation of apoptotic cell phagocytosis and amyloid-beta peptide brain uptake and various myopathies [65][66][67] .…”

Section: Circulating Markers Of Inflammation and Immune Activation Co...mentioning

confidence: 99%

Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19

Peluso,

Ryder,

Flavell

et al. 2023

Preprint

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The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection. We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue forin situhybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms. We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations.

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Section: Circulating Markers Of Inflammation and Immune Activation Co...mentioning

confidence: 99%

Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19

Peluso,

Ryder,

Flavell

et al. 2023

Preprint

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“…Thus, GFAP appears to function as a scaffolding protein to mediate the proper surface expression of both GLT‐1 and GLAST and protect against glutamate‐mediated excitotoxicity in response to stress. Another putative mechanism contributing to the dysregulation of the glutamate transporter is mediated by epigenetic factors such as DNA methylation, which have only recently garnered attention in astrocytes in patients with MDD (Ernst, Chen, & Turecki, ; Jakovcevski, Akbarian, & Di Benedetto, ; Zhang et al, ). Aberrant changes in DNA methylation may lead to a marked reduction in the expression of astrocyte‐specific genes, including genes encoding GLAST in the PFC of post‐mortem tissue from depressed suicides (Nagy et al, ).…”

Section: Glutamate Homeostasismentioning

confidence: 99%

An astroglial basis of major depressive disorder? An overview

Wang

Jie

Liu

et al. 2017

Glia

172

125

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Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.

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“…Specificity of epigenetic changes in astrocytes as compared to changes in neurons is underscored by astrocyte-specific higher or lower expression of some of the enzymes that are in charge of executing epigenetic modifications, astrocytes featuring higher mRNA expression of histone deacetylase Hdac8, sirtuin Sirt8, histone methyl-transferase Mll3 or histone demethylase Kdm5d, while underexpressing histone deacetylase Hdac5, Hdac11 or histone demethylase Kdm2b (Zhang et al, 2014;Jakovcevski et al, 2016). This capability of astrocytes to differentially contribute to epigenetic changes may be of great relevance to the vulnerability to stress-related disorders and depression since disturbances in the expression of epigenetic enzymes and in the epigenetic changes themselves have been found to distinguish specific brain regions of subjects with depression as compared to non-psychiatric human subjects (Lopizzo et al, 2015;Jakovcevski et al, 2016). Other studies have pointed to factors involved in regulating the transcription of glutamate transporters such as the astrocyte-elevated gene which acts as corepressor of factor YY1 to repress the transcription of GLT-1 and diminish glutamate uptake by astrocytes.…”

Section: Astrocyte Epigenetic Markers In Stress and Depressionmentioning

confidence: 99%

Astroglia in the Vulnerability to and Maintenance of Stress-Mediated Neuropathology and Depression

Miguel-Hidalgo

2022

Front. Cell. Neurosci.

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Significant stress exposure and psychiatric depression are associated with morphological, biochemical, and physiological disturbances of astrocytes in specific brain regions relevant to the pathophysiology of those disorders, suggesting that astrocytes are involved in the mechanisms underlying the vulnerability to or maintenance of stress-related neuropathology and depression. To understand those mechanisms a variety of studies have probed the effect of various modalities of stress exposure on the metabolism, gene expression and plasticity of astrocytes. These studies have uncovered the participation of various cellular pathways, such as those for intracellular calcium regulation, neuroimmune responses, extracellular ionic regulation, gap junctions-based cellular communication, and regulation of neurotransmitter and gliotransmitter release and uptake. More recently epigenetic modifications resulting from exposure to chronic forms of stress or to early life adversity have been suggested to affect not only neuronal mechanisms but also gene expression and physiology of astrocytes and other glial cells. However, much remains to be learned to understand the specific role of those and other modifications in the astroglial contribution to the vulnerability to and maintenance of stress-related disorders and depression, and for leveraging that knowledge to achieve more effective psychiatric therapies.

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Pharmacological modulation of astrocytes and the role of cell type-specific histone modifications for the treatment of mood disorders

Cited by 9 publications

References 40 publications

Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19

Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19

An astroglial basis of major depressive disorder? An overview

Astroglia in the Vulnerability to and Maintenance of Stress-Mediated Neuropathology and Depression

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