Role of Astrocytes in Major Neuropsychiatric Disorders

Zhang, Xiaolu; Alnafisah, Rawan; Hamoud, Abdul‐rizaq; Shukla, Rammohan; Wen, Zhexing; McCullumsmith, Robert E.; O’Donovan, Sinead M.

doi:10.1007/s11064-020-03212-x

Cited by 28 publications

(30 citation statements)

References 172 publications

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“…The set of genes representing the "common" astrocyte genes were the most frequently enriched across diseases, including Alzheimer's disease, epilepsy, schizophrenia, and depression. This is in line with findings that astrocytes play important roles in the pathophysiology of these disorders [65]. The AST4 and AST5 subtypes, thought to represent progenitor astrocytes and intermediate (progenitor-mature) astrocyte populations, respectively [74], were also enriched across depression datasets.…”

Section: Astrocyte Subset Genes Most Affected In Neuropsychiatric Diseasesupporting

confidence: 88%

“…Astrocytes play an important, albeit still poorly understood role in many neurological and psychiatric diseases [1][2][3]65]. Although postmortem studies generally support altered astrocyte expression and morphology in neurological and psychiatric diseases [6,7,10,[20][21][22][23][24][25][26][27][28][29], many studies have shown conflicting findings [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] or report no changes in astrocytes in disease [27,[30][31][32][33][34][35].…”

Section: Discussionmentioning

confidence: 99%

“…To improve our understanding of how astrocytes are altered in the brain in disease and better our understanding of the effects of medications on astrocytes in the brain, we carried out bioinformatic analysis, taking advantage of emerging single-cell RNAseq datasets that define murine astrocyte subtypes, and human CNS disorder transcriptomic datasets. As unique molecular signatures for different subtypes of human astrocytes have yet to be elucidated [65,66], we instead used signatures for five different astrocyte subtypes (AST1-5) and a "common" astrocyte signature derived from mouse brain [74].…”

Section: Discussionmentioning

confidence: 99%

“…There are also different "types" of astrocytes that can have potentially different responses to injury. These subtypes are classified based on cellular morphology (e.g., protoplasmic, fibrous, bushy), location (e.g., frontal cortex, hippocampus, cerebellum) and primary functions (e.g., metabolic, structural, signaling) [65]. However, our understanding of the different types of astrocytes in humans and their roles in CNS disorders is still limited [65,66].…”

Section: Introductionmentioning

confidence: 99%

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Assessing the relationships between neurological and psychiatric diseases with astrocyte subtypes and psychotropic medications

Zhang

Wolfinger

Shukla

et al. 2021

Preprint

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Astrocytes have many important functions in the brain, but their roles in CNS disorders and their responses to psychotropic medications are still being elucidated. In this study, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, neurological and psychiatric diseases, and psychotropic medications. We also carried out qPCR analyses and "look-up" studies to further assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified differential gene enrichment of different astrocyte subtypes in CNS disorders. The "common" astrocyte subtype was the most frequently enriched across disorders, but the highest level of enrichment was found in depression, supporting a role for astrocytes in this disorder. We also identified common enrichment of metabolic and signal transduction-related biological processes in astrocyte subtypes and CNS disorders. However, enrichment of different psychotropic medications, including antipsychotics, antidepressants, and mood stabilizers, was limited in astrocyte subtypes. These results were confirmed by "look-up" studies and qPCR analysis, which also reported little effect of common psychotropic medications on astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in CNS disorders and offers insights into targeting astrocytes therapeutically.

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Section: Astrocyte Subset Genes Most Affected In Neuropsychiatric Diseasesupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessing the relationships between neurological and psychiatric diseases with astrocyte subtypes and psychotropic medications

Zhang

Wolfinger

Shukla

et al. 2021

Preprint

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“…MRS Glu and mI are believed to index astroglial dysfunction and distress 57,58 . Astroglial dysfunction is a well-documented feature of mood disorders but may be particularly relevant to the inflammatory subtype of MD 59,60 . The precise nature of the astroglial dysfunction in the inflammatory subtype of depression is not yet fully clarified.…”

Section: Discussionmentioning

confidence: 99%

Kynurenines Increase MRS Metabolites in Basal Ganglia and Decrease Resting State Connectivity in Frontostriatal Reward Circuitry in Depression

Chen

Beltran

Tsygankova

et al. 2021

Preprint

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Inflammation is associated with depressive symptoms including anhedonia in patients with major depression. Nevertheless, the mechanisms by which peripheral inflammatory signals are communicated to the brain to influence central nervous system (CNS) function has yet to be fully elucidated. Based on laboratory animal studies, molecules of the kynurenine pathway (KP), which is activated by inflammation, can readily enter the brain, and generate metabolites that can alter neuronal and glial function, leading to behavioral changes. We therefore examined the relationship between KP metabolites in the plasma and cerebrospinal fluid (CSF) and brain chemistry and neural network function using multi-modal neuroimaging in 49 unmedicated, depressed subjects. CNS measures included 1) biochemical markers of glial dysfunction including glutamate (Glu) and myo-inositol (mI) in the left basal ganglia (LBG) using magnetic resonance spectroscopy (MRS); 2) local activity coherence (regional homogeneity, ReHo) and functional connectivity using resting-state functional magnetic resonance imaging; and 3) anhedonia from the Inventory for Depressive Symptoms-Self Reported. Plasma quinolinic acid (QA) was associated with increases and kynurenic acid (KYNA) and KYNA/QA with decreases in LBG Glu. Plasma kynurenine/tryptophan and CSF 3-hydroxy kynurenine (3HK) were associated with increases in LBG mI. Plasma and CSF KP were associated with decreases in ReHo in LBG and dorsomedial prefrontal cortex (DMPFC), and impaired functional connectivity between these two brain regions. DMPFC-BG connectivity mediated the effect of plasma and CSF KP metabolites on anhedonia. These findings highlight the contribution of KP metabolites to glial and neuronal dysfunction and ultimately behavior in depression.

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Characterization of Astrocyte Morphology and Function Using a Fast and Reliable Tissue Clearing Technique

et al. 2021

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Astrocytic processes interact with synapses throughout the brain modulating neurotransmitter signaling and synaptic communication. During conditions such as exposure to drugs of abuse and neurological diseases, astrocytes respond by altering their morphological and functional properties. Reactive astrocyte phenotypes exhibit a bushy morphology with altered soma volume and an increased number of processes compared to resting astrocytes. The reactive astrocytic phenotype also overexpresses proteins one of which can be glial fibrillary acidic protein (GFAP). Fluorescence microscopy on thin tissue sections (<20 μm) requires reconstruction, often through multiple sections, to delineate the full astrocytic morphology. In contrast, tissue clearing methods have been developed that enable imaging of larger sections including the whole brain, providing an opportunity to see in-depth changes in single cell structure. In this article, a detailed protocol for studying astrocyte morphology using tissue clearing and subsequent imaging of whole brains as well as region-specific slices is provided. This method is ideal for understanding the effect of different physiological conditions on astrocyte morphology. A standard biochemistry laboratory has the resources to accomplish tissue clearing using this protocol and most universities have the required imaging facilities. Protocols to study brains from both genetically modified mice that contain an astrocyte-specific marker and from wild-type mice using antibody labeling steps after tissue clearing are provided. We also describe general protocols to conduct fluorescence imaging of astrocytes in cleared tissue to characterize their morphology. This protocol could be useful for researchers working in the rapidly growing field of astrocyte biology.

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Role of Astrocytes in Major Neuropsychiatric Disorders

Cited by 28 publications

References 172 publications

Assessing the relationships between neurological and psychiatric diseases with astrocyte subtypes and psychotropic medications

Assessing the relationships between neurological and psychiatric diseases with astrocyte subtypes and psychotropic medications

Kynurenines Increase MRS Metabolites in Basal Ganglia and Decrease Resting State Connectivity in Frontostriatal Reward Circuitry in Depression

Characterization of Astrocyte Morphology and Function Using a Fast and Reliable Tissue Clearing Technique

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