Astrocyte function from information processing to cognition and cognitive impairment

Santello, Mirko; Toni, Nicolas; Volterra, Andrea

doi:10.1038/s41593-018-0325-8

Cited by 528 publications

(454 citation statements)

References 150 publications

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“…Therefore, change in the expression of genes associated with astrocyte function cannot be attributed directly to the replication of PrP Sc by astrocytes. In homeostatic state, astrocytes are responsible for a variety of physiological functions including modulation of neurotransmission, formation and elimination of synapses, regulation of blood flow, supplying energy and providing metabolic support to neurons, maintaining the blood-brain-barrier, synthesis of cholesterol and much more [108, 109]. Because the representation of genes that report on astrocytic function in the Neuroinflammation panel is limited, the current work cannot identify specific functions that are disrupted or upregulated in the reactive astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Loss of region-specific glial homeostatic signature in prion diseases

Makarava

Chang

Molesworth

et al. 2019

Preprint

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13Background Chronic neuroinflammation is recognized as a major neuropathological hallmark in 14 a broad spectrum of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal 15 Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and 16 astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic 17 neurodegeneration, transform into reactive phenotypes in a region-and disease-specific manner. 18 Little is known about region-specific identity of glia in prion diseases. The current study was 19 designed to determine whether the region-specific homeostatic signature of glia changes with the 20 progression of prion diseases, and whether these changes occur in a region-dependent or universal 21 manner. Also of interest was whether different prion strains give rise to different reactive 22 phenotypes.23 Methods To answer these questions, we analyzed gene expression in thalamus, cortex, 24 hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using Nanostring 25 Neuroinflammation panel at subclinical, early clinical and advanced stages of the disease. 26 ResultsWe found that at the preclinical stage of the disease, region-specific homeostatic identities 27 were preserved. However, with the appearance of clinical signs, region-specific signatures were 28 partially lost and replaced with a neuroinflammation signature. While the same sets of genes were 29 activated by both prion strains, the timing of neuroinflammation and the degree of activation in 30 different brain regions was strain-specific. Changes in astrocyte function scored at the top of 31 activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway 32 responded to prion infection prior to activated microglia or neuron and neurotransmission 33 pathways. 34Conclusions The current work established neuroinflammation gene expression signature 35 associated with prion diseases. Our results illustrate that with the disease progression, the region-36 specific homeostatic transcriptome signatures are replaced by region-independent 37 neuroinflammation signature, which was common for prion strains with different cell tropism. The 38 prion-associated neuroinflammation signature identified in the current study overlapped only 39 partially with the microglia degenerative phenotype and the disease-associated microglia 40 phenotype reported for animal models of other neurodegenerative diseases. 41 3 Background 45 Chronic neuroinflammation is recognized as one of the major neuropathological hallmarks 46 of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia, 47 Amyotrophic Lateral Sclerosis, and prion diseases [1]. Chronic neuroinflammation manifests itself 48 as a sustained activation of glial cells and the transformation of their homeostatic phenotype into 49 reactive phenotypes [2, 3]. Transcriptome analysis and single-cell RNA-sequencing revealed 50 considerable region-specific homeosta...

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Section: Discussionmentioning

confidence: 99%

Loss of region-specific glial homeostatic signature in prion diseases

Makarava

Chang

Molesworth

et al. 2019

Preprint

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“…Astrocytes are able to sense and integrate a multitude of signals from the endogenous and exogenous environment and use this information to modulate neuronal function. They are involved in many different processes crucial for brain and cognitive functioning (Santello, Toni, & Volterra, ) including glutamate recycling (Sonnewald, Westergaard, & Schousboe, ), myelination (Camargo et al, ; Kıray, Lindsay, Hosseinzadeh, & Barnett, ), energy metabolism (Bélanger, Allaman, & Magistretti, ), and synaptic development and functioning (Allen, ; Allen & Eroglu, ). It has been known that astrocytes promote synaptogenesis during development (Allen, ), and emerging evidence shows that astrocytes also control dendritic maturation and synaptic integration of adult newborn neurons in the hippocampus (Kempermann, ; Sultan et al, ).…”

Section: Introductionmentioning

confidence: 99%

The involvement of astrocytes in early‐life adversity induced programming of the brain

Abbink

Deijk

Heine

et al. 2019

Glia

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Early‐life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early‐life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes.

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“…Here, polygenic signatures of astrocytes were consistently associated to depression relevant shifts in both in-vivo imaging phenotypes and ex-vivo profiles of gene downregulation (Figure 4). Astrocytes influence synapse formation and elimination, as well as modulate neuronal communication, in part, through glutamate release and NMDAR receptor activation 57,58 . Accordingly, depression related abnormalities in astrocytes may be involved in reduced glutamate levels in PFC and ACC of patients 12 .…”

Section: Discussionmentioning

confidence: 99%

Convergent molecular, cellular, and neural signatures of major depressive disorder

Anderson

Collins

Kong

et al. 2020

Preprint

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Figures Count: Main text (6), Supplementary (9) Word count: Abstract (244), Introduction (821), Results (2,553), Discussion (1,689) References: Main text (77), Methods only (29) Supplementary Data Tables: 15 Code repository: 1 Key Findings 1. Major depressive disorder and negative affect are associated with replicable profiles of cortical anatomy and function across independent population-level neuroimaging datasets (combined N≥23,723). 2. Somatostatin interneurons are consistent spatial transcriptional associates of in-vivo depression-linked imaging phenotypes. 3. Integrative single-cell gene expression analysis associate somatostatin interneurons and astrocytes with both in-vivo depression-linked imaging and ex-vivo gene downregulation in independent MDD cortical tissue samples. 4. Transcriptional correlates of in-vivo depression imaging phenotypes selectively capture gene downregulation in post-mortem tissue samples from patients with depression, but not other psychiatric disorders.5. Indicating that some cell classes are preferentially sensitive to inherited disease liability, genome-wide risk for depression is enriched among interneurons, but not glia.6. Gene associates of depression-linked anatomy and function identify specific neurotransmitter systems, molecular signaling pathways, and receptors, suggesting possible targets for pharmaceutical intervention. AbstractMajor depressive disorder emerges from the complex interactions of biological systems that span across genes and molecules through cells, circuits, networks, and behavior.Establishing how neurobiological processes coalesce to contribute to the onset and maintenance of depression requires a multi-scale approach, encompassing measures of brain structure and function as well as genetic and cell-specific genomic data. Here, we examined anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Genome Superstruct Project, and ENIGMA (combined N≥23,723). Integrative analyses incorporated measures of cortical gene expression, post-mortem patient transcriptional data, depression GWAS, and single-cell transcription. Neuroimaging correlates of depression and negative affect were consistent across the three independent datasets. Linking ex-vivo gene downregulation with in-vivo neuroimaging, we found that genomic correlates of depression-linked neuroimaging phenotypes tracked gene downregulation in post-mortem cortical tissue samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data implicated somatostatin interneurons and astrocytes as consistent cell associates of depression, through both in-vivo imaging and ex-vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multi-scale appro...

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Astrocyte function from information processing to cognition and cognitive impairment

Cited by 528 publications

References 150 publications

Loss of region-specific glial homeostatic signature in prion diseases

Loss of region-specific glial homeostatic signature in prion diseases

The involvement of astrocytes in early‐life adversity induced programming of the brain

Convergent molecular, cellular, and neural signatures of major depressive disorder

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