Epigenetics and the Modulation of Neuroinflammation

Garden, Gwenn A.

doi:10.1007/s13311-013-0207-4

Cited by 59 publications

(39 citation statements)

References 55 publications

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“…In pathological contexts, both cell-extrinsic environmental cues as well as epigenetic modifications can shape the reactive responses exhibited by microglia (Ransohoff and Perry, 2009; Garden, 2013). However, the regulatory factors that determine basal microglial phenotype are largely unknown.…”

Section: Resultsmentioning

confidence: 99%

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Biase

Schuebel

Fusfeld

et al. 2017

Neuron

347

348

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SUMMARY Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei. Region-specific phenotypes of BG microglia emerged during the second postnatal week and were re-established following genetic or pharmacological microglial ablation and repopulation in the adult, indicating that local cues play an ongoing role in shaping microglial diversity. These findings demonstrate that microglia in the healthy brain exhibit a spectrum of distinct functional states and provide a critical foundation for defining microglial contributions to BG circuit function.

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Section: Resultsmentioning

confidence: 99%

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Biase

Schuebel

Fusfeld

et al. 2017

Neuron

347

348

View full text Add to dashboard Cite

show abstract

“…The molecular regulation of neuroinflammation is strongly influenced by epigenetic mechanisms (i.e. by DNA methylation, histone modification, and noncoding RNA) …”

Section: Neuro‐immuno‐endocrinological Approachmentioning

confidence: 99%

Biological hypotheses and biomarkers of bipolar disorder

Sigitova

Fišar

Hroudová

et al. 2017

Psychiatry Clin Neurosci

192

117

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The most common mood disorders are major depressive disorders and bipolar disorders (BD). The pathophysiology of BD is complex, multifactorial, and not fully understood. Creation of new hypotheses in the field gives impetus for studies and for finding new biomarkers for BD. Conversely, new biomarkers facilitate not only diagnosis of a disorder and monitoring of biological effects of treatment, but also formulation of new hypotheses about the causes and pathophysiology of the BD. BD is characterized by multiple associations between disturbed brain development, neuroplasticity, and chronobiology, caused by: genetic and environmental factors; defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways; oxidative and nitrosative stress; cellular bioenergetics; and membrane or vesicular transport. Current biological hypotheses of BD are summarized, including related pathophysiological processes and key biomarkers, which have been associated with changes in genetics, systems of neurotransmitter and neurotrophic factors, neuroinflammation, autoimmunity, cytokines, stress axis activity, chronobiology, oxidative stress, and mitochondrial dysfunctions. Here we also discuss the therapeutic hypotheses and mechanisms of the switch between depressive and manic state.

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“…The mechanism underlying the observed prolonged effects of prenatal stress on microglia has not yet been identified. Aside from changes in gene transcription, there are some data to suggest that epigenetic mechanisms involving DNA methylation, histone modifications, and noncoding RNAs play a role in modulating the inflammatory response of microglia (Garden, 2013). Prenatal stress induced impairments in microglia signaling.…”

Section: Obuchowicz Et Almentioning

confidence: 99%

Imipramine and Venlafaxine Differentially Affect Primary Glial Cultures of Prenatally Stressed Rats

et al. 2020

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Here, we examine the effects of prenatal administration of two antidepressantsimipramine (IMI) and venlafaxine (VEN)-on morphology and activity of a primary glial culture. Microglia are targeted by antidepressants used for antenatal depression and are important regulators of central nervous system development. In this study, female Wistar rats were assigned to one of four groups: a control group that received water ad libitum (1), and groups that received additionally once daily either water (2), IMI (10 mg/kg) (3), or VEN (20 mg/kg) (4) by oral gavage from gestation day 7 to 22. Oral gavage administration induced prenatal stress. Cell cultures were obtained from the brains of 1-day-old pups. Prenatal stress caused a disturbance of sensorimotor function in pups. Prenatal stress also produced alterations in the glial cultures, specifically, an increased percentage of microglia in the mixed glial cultures and an increased percentage of dead cells. Moreover, increased levels of IL1-b, TNF-a, NO, and an increased expression of CX3CR1 mRNA were found in microglia. However, the ratio of Bax/Bcl2 mRNA was reduced. Prenatal stress increased the vulnerability of microglia to lipopolysaccharide (LPS). The mixed glial culture derived from pups exposed to IMI showed greater morphological changes and the highest percentage of microglia. Microglia were characterized by the largest increase in the production of pro-inflammatory cytokines and NO, and the greatest reduction in the expression of CX3CR1 mRNA. Exposure to IMI reduced the effects of LPS on IL-1b production and Bax/Bcl2 mRNA, and exacerbated the effects of LPS on CX3CR1 mRNA expression. Prenatal administration of VEN induced protective effects on microglia, as measured by all studied parameters. Taken together, our data suggest that, by disturbing microglia function, exposure to even mild forms of chronic prenatal stress may predispose individuals to psychiatric or neurodevelopmental disorders. These data also indicate that chronic mild stress sensitizes microglia to immune challenges, which may lead to enhanced neuronal damage in the embryonic brain. The observed detrimental effects of IMI on microglial activity under conditions of prenatal stress may help to explain the teratogenic effects of IMI reported in the literature.

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Epigenetics and the Modulation of Neuroinflammation

Cited by 59 publications

References 55 publications

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Biological hypotheses and biomarkers of bipolar disorder

Imipramine and Venlafaxine Differentially Affect Primary Glial Cultures of Prenatally Stressed Rats

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