Astrocytic‐neuronal crosstalk gets jammed: Alternative perspectives on the onset of neuropsychiatric disorders

Roman, Celia; Egert, Luisa; Benedetto, Barbara Di

doi:10.1111/ejn.14900

Cited by 16 publications

(13 citation statements)

References 119 publications

(156 reference statements)

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“…Astrocytes may also use another phagocytic pathway, via receptors Multiple EGF-like domains 10 (MEG10) and MER Tyrosine Kinase (MERTK), which is independent of C1q. Both pathways mediate synaptic pruning during development [ 26 ]. Support comes from findings of excess synapses in MEGF10 and MERTK deficient mice, reflecting missing circuit refinement [ 26 ].…”

Section: The Emerging Role Of Astrocytes In Synaptic Pruningmentioning

confidence: 99%

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Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Germann

Brederoo²,

Sommer

2021

Current Opinion in Psychiatry

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Purpose of review Excessive synaptic pruning has first been suggested by Irwin Feinberg (1982) as an important pillar in the pathophysiology in schizophrenia (SCZ). This article reviews recent developments highlighting factors implicated in aberrant synaptic pruning and its contribution to disease onset and emergence of cognitive symptoms in SCZ. Unraveling these factors provides new insights for potential prevention and treatment strategies for psychotic disorders. Recent findings Increased pruning in SCZ was recently confirmed by a positron emission tomography-study employing the novel tracer [11C]UCB-J, demonstrating the consequential loss of synaptic density. Recent evidence supports the contributing role of astrocytes and increased complement-mediated microglial pruning in disease onset and cognitive symptoms in SCZ. Increased microglial pruning is mediated specifically by C4. Furthermore, environmental factors (e.g., infections and stress) can lead to dysbiosis which was recently linked to microglial activation and pruning in SCZ. Summary Recent findings render the pruning machinery a potential target for early treatment and prevention in individuals at high risk for SCZ. Minocycline can improve cognition in SCZ, probably by reducing excessive pruning. Probiotics might also have beneficial effects on cognition, although recent findings are not encouraging. N-acetyl-cysteine recovers functional connectivity in SCZ both in vitro and in vivo, making it an interesting candidate.

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Section: The Emerging Role Of Astrocytes In Synaptic Pruningmentioning

confidence: 99%

“…Both pathways mediate synaptic pruning during development [ 26 ]. Support comes from findings of excess synapses in MEGF10 and MERTK deficient mice, reflecting missing circuit refinement [ 26 ].…”

Section: The Emerging Role Of Astrocytes In Synaptic Pruningmentioning

confidence: 99%

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Germann

Brederoo²,

Sommer

2021

Current Opinion in Psychiatry

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“…In conclusion, the present study showed that cocaine potentiated the inflammatory response in LPS and IFNγ-stimulated astroglia-like cells under a diseased-state. Since astrocytes modulate the synaptic cross-talk in vivo ( 7 ), excess release of NO by activated astrocytes with cocaine could result in dysfunction of neurons and lead to the development or exacerbation of several CNS disorders ( 44 ). The involvement of NMDA receptors in excess NO production, their expression in astrocytes ( 11 ) and glutamatergic neurons highlights the possibility of using NMDA antagonists as a means of regulating NO levels in the body; which may aid in delaying the onset or progression of several CNS diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Astrocytes are one of the most abundant cell-types in the CNS, functioning in neuronal survival and maintenance of fundamental patterns of circuitry ( 6 ). It is well established that astrocytes mediate synaptic cross-talk ( 7 ), suggesting that astrocytes may be just as important as neurons in research on cocaine abuse. Owing to their abundance in the majority of regions of the brain ( 8 ), astrocytes may be the first type of cells to experience the toxic effects of cocaine through decreased mitochondrial membrane potential, resulting in a hypoxia-like state in cells, with regard to being unable to reduce oxygen to water.…”

Section: Introductionmentioning

confidence: 99%

Cocaine potentiates an inflammatory response in C6 astroglia‑like cells

et al. 2021

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Cocaine is a highly addictive drug that mediates its effect through altering dopamine metabolism in the central nervous system (CNS), resulting in a feeling of euphoria. Owing to its high lipophilicity, cocaine easily crosses the blood brain barrier of the CNS and reaches various domains of the brain, where it can trigger cellular damage. Cocaine-induced CNS damage may arise due to increased levels of free radicals and nitric oxide (NO) in immunecompetent astroglial cells. In the present study, the potential ability of cocaine to exacerbate the production of inflammatory products, primarily superoxide free radicals (O 2 - ), hydrogen peroxide (H 2 O 2 ) and NO/nitrite (NO 2 - ) was examined in rat C6 astroglia-like cells challenged with lipopolysaccharide (LPS), a bacterial endotoxin, and interferon gamma (IFNγ), a pro-inflammatory cytokine. Furthermore, the role of cocaine in increasing the expression of hypoxia inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF) in cells was also determined. First, the viability of the cells was assessed when treated with cocaine (0.5-7 mM) for 24 and 48 h. The results showed that cocaine toxicity was both time and dose-dependent. In subsequent studies, cells were challenged with or without LPS and IFNγ, followed by co-treatment with cocaine (1-4 mM) for 24 h. Cocaine treatment did not increase O 2 - or H 2 O 2 production in the challenged or unchallenged cells. Similarly, cocaine treatment did not increase NO/NO 2 - production in the unchallenged cells; however, NO/NO 2 - levels in the challenged cells was increased 40-50-fold upon cocaine treatment compared with the corresponding unchallenged group. The HIF-1α and VEGF levels were significantly increased in the challenged cells at higher cocaine doses compared with the unchallenged cells. Since high concentrations of NO are associated with inflammation, the high levels of NO production observed in the present study suggested that cocaine may have potentiated the inflammatory response in the challenged C6 astroglia-like cells.

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“…In addition see also recent findings suggestive of purinergic signaling from astrocytes to microglia upon histaminergic stimulation (Xia et al, 2021). Moreover, changes in astrocyteneuronal crosstalk have been implicated in the development of mental disorders, including depression, ASD and schizophrenia (Roman et al, 2020). However, to our knowledge, there are no studies that have investigated the specific role of histamine in directly modulating astrocytic behavior contributing to neurodevelopmental disorders.…”

Section: Histamine's Regulation Of Astrocytesmentioning

confidence: 99%

Histamine, Neuroinflammation and Neurodevelopment: A Review

Carthy

Ellender

2021

Front. Neurosci.

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The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette’s syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.

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Astrocytic‐neuronal crosstalk gets jammed: Alternative perspectives on the onset of neuropsychiatric disorders

Cited by 16 publications

References 119 publications

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders

Cocaine potentiates an inflammatory response in C6 astroglia‑like cells

Histamine, Neuroinflammation and Neurodevelopment: A Review

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