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Science (New York, N.Y.) Nov 2022Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse...
Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse central nervous system (CNS). We identified shared and region-specific astrocytic genes and functions and explored the cellular origins of their regional diversity. We identified gene networks correlated with astrocyte morphology, several of which unexpectedly contained Alzheimer's disease (AD) risk genes. CRISPR/Cas9-mediated reduction of candidate genes reduced astrocyte morphological complexity and resulted in cognitive deficits. The same genes were down-regulated in human AD, in an AD mouse model that displayed reduced astrocyte morphology, and in other human brain disorders. We thus provide comprehensive molecular data on astrocyte diversity and mechanisms across the CNS and on the molecular basis of astrocyte morphology in health and disease.
Topics: Animals; Humans; Mice; Alzheimer Disease; Astrocytes; Disease Models, Animal; Central Nervous System; Transcriptome
PubMed: 36378959
DOI: 10.1126/science.adc9020 -
Neuron Nov 2020Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated... (Review)
Review
Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.
Topics: Animals; Astrocytes; Cell Communication; Central Nervous System; Humans; Inflammation; Models, Neurological
PubMed: 32898475
DOI: 10.1016/j.neuron.2020.08.012 -
Nature Reviews. Drug Discovery May 2022Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous... (Review)
Review
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell-cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.
Topics: Astrocytes; Cell Communication; Glutamic Acid; Humans; Multiple Sclerosis; Nervous System Diseases
PubMed: 35173313
DOI: 10.1038/s41573-022-00390-x -
Trends in Immunology Sep 2020Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple... (Review)
Review
Astrocytes are the most abundant cell type in the central nervous system (CNS), performing complex functions in health and disease. It is now clear that multiple astrocyte subsets or activation states (plastic phenotypes driven by intrinsic and extrinsic cues) can be identified, associated to specific genomic programs and functions. The characterization of these subsets and the mechanisms that control them may provide unique insights into the pathogenesis of neurologic diseases, and identify potential targets for therapeutic intervention. In this article, we provide an overview of the role of astrocytes in CNS inflammation, highlighting recent discoveries on astrocyte subsets and the mechanisms that control them.
Topics: Astrocytes; Central Nervous System; Humans; Inflammation; Nervous System Diseases
PubMed: 32800705
DOI: 10.1016/j.it.2020.07.007 -
Trends in Immunology Sep 2020Astrocytes are neural parenchymal cells that ubiquitously tile the central nervous system (CNS). In addition to playing essential roles in healthy tissue, astrocytes... (Review)
Review
Astrocytes are neural parenchymal cells that ubiquitously tile the central nervous system (CNS). In addition to playing essential roles in healthy tissue, astrocytes exhibit an evolutionarily ancient response to all CNS insults, referred to as astrocyte reactivity. Long regarded as passive and homogeneous, astrocyte reactivity is being revealed as a heterogeneous and functionally powerful component of mammalian CNS innate immunity. Nevertheless, concepts about what astrocyte reactivity comprises and what it does are incomplete and sometimes controversial. This review discusses the goal of differentiating reactive astrocyte subtypes and states based on composite pictures of molecular expression, cell morphology, cellular interactions, proliferative state, normal functions, and disease-induced dysfunctions. A working model and conceptual framework is presented for characterizing the diversity of astrocyte reactivity.
Topics: Animals; Astrocytes; Cell Communication; Cell Differentiation; Central Nervous System; Humans; Immunity, Innate
PubMed: 32819810
DOI: 10.1016/j.it.2020.07.004 -
Nature Reviews. Neurology Dec 2022Epilepsy affects ~65 million people worldwide. First-line treatment options include >20 antiseizure medications, but seizure control is not achieved in approximately... (Review)
Review
Epilepsy affects ~65 million people worldwide. First-line treatment options include >20 antiseizure medications, but seizure control is not achieved in approximately one-third of patients. Antiseizure medications act primarily on neurons and can provide symptomatic control of seizures, but do not alter the onset and progression of epilepsy and can cause serious adverse effects. Therefore, medications with new cellular and molecular targets and mechanisms of action are needed. Accumulating evidence indicates that astrocytes are crucial to the pathophysiological mechanisms of epilepsy, raising the possibility that these cells could be novel therapeutic targets. In this Review, we discuss how dysregulation of key astrocyte functions - gliotransmission, cell metabolism and immune function - contribute to the development and progression of hyperexcitability in epilepsy. We consider strategies to mitigate astrocyte dysfunction in each of these areas, and provide an overview of how astrocyte activation states can be monitored in vivo not only to assess their contribution to disease but also to identify markers of disease processes and treatment effects. Improved understanding of the roles of astrocytes in epilepsy has the potential to lead to novel therapies to prevent the initiation and progression of epilepsy.
Topics: Humans; Astrocytes; Epilepsy; Seizures; Neurons
PubMed: 36280704
DOI: 10.1038/s41582-022-00727-5 -
Nature Apr 2023Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their...
Astrocytes and neurons extensively interact in the brain. Identifying astrocyte and neuron proteomes is essential for elucidating the protein networks that dictate their respective contributions to physiology and disease. Here we used cell-specific and subcompartment-specific proximity-dependent biotinylation to study the proteomes of striatal astrocytes and neurons in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and neurons to discover how these cells differ at the protein level in their signalling machinery. We also assessed subcellular compartments of astrocytes, including end feet and fine processes, to reveal their subproteomes and the molecular basis of essential astrocyte signalling and homeostatic functions. Notably, SAPAP3 (encoded by Dlgap3), which is associated with obsessive-compulsive disorder (OCD) and repetitive behaviours, was detected at high levels in striatal astrocytes and was enriched within specific astrocyte subcompartments where it regulated actin cytoskeleton organization. Furthermore, genetic rescue experiments combined with behavioural analyses and molecular assessments in a mouse model of OCD lacking SAPAP3 revealed distinct contributions of astrocytic and neuronal SAPAP3 to repetitive and anxiety-related OCD-like phenotypes. Our data define how astrocytes and neurons differ at the protein level and in their major signalling pathways. Moreover, they reveal how astrocyte subproteomes vary between physiological subcompartments and how both astrocyte and neuronal SAPAP3 mechanisms contribute to OCD phenotypes in mice. Our data indicate that therapeutic strategies that target both astrocytes and neurons may be useful to explore in OCD and potentially other brain disorders.
Topics: Animals; Mice; Astrocytes; Neurons; Obsessive-Compulsive Disorder; Proteome; Biotinylation; Cell Membrane; Signal Transduction; Cytosol; Homeostasis; Phenotype; Actin Cytoskeleton
PubMed: 37046092
DOI: 10.1038/s41586-023-05927-7 -
JCI Insight Dec 2021Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and...
Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and depressive mice. Pyroptosis is a recently discovered form of programmed cell death depending on Caspase-gasdermin D (Casp-GSDMD), which is involved in multiple neuropsychiatric diseases. However, the involvement of pyroptosis in the onset of MDD and glial pathological injury remains obscure. Here, we observed that depressive mice showed astrocytic pyroptosis, which was responsible for astrocyte loss, and selective serotonin reuptake inhibitor (SSRI) treatment could attenuate the pyroptosis induced by the chronic mild stress (CMS) model. Genetic KO of GSDMD, Casp-1, and astrocytic NOD-like receptor protein 3 (NLRP3) inflammasome in mice alleviated depression-like behaviors and inhibited the pyroptosis-associated protein expression. In contrast, overexpression of astrocytic GSDMD-N-terminal domain (GSDMD-N) in the hippocampus could abolish the improvement of behavioral alterations in GSDMD-deficient mice. This work illustrates that targeting the NLRP3/Casp-1/GSDMD-mediated pyroptosis may provide potential therapeutic benefits to stress-related astrocyte loss in the pathogenesis of depression.
Topics: Animals; Astrocytes; Caspase 1; Depression; Disease Models, Animal; Humans; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 34877938
DOI: 10.1172/jci.insight.146852 -
Nature Metabolism Mar 2023Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low...
Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
Topics: Mice; Animals; Neuroinflammatory Diseases; Astrocytes; Alzheimer Disease; Fatty Acids; Mitochondria
PubMed: 36959514
DOI: 10.1038/s42255-023-00756-4 -
Neuron Apr 2023Social experience is essential for the development and maintenance of higher-order brain function. Social deprivation results in a host of cognitive deficits, and...
Social experience is essential for the development and maintenance of higher-order brain function. Social deprivation results in a host of cognitive deficits, and cellular studies have largely focused on associated neuronal dysregulation; how astrocyte function is impacted by social deprivation is unknown. Here, we show that hippocampal astrocytes from juvenile mice subjected to social isolation exhibit increased Ca activity and global changes in gene expression. We found that the Ca channel TRPA1 is upregulated in astrocytes after social deprivation and astrocyte-specific deletion of TRPA1 reverses the physiological and cognitive deficits associated with social deprivation. Mechanistically, TRPA1 inhibition of hippocampal circuits is mediated by a parallel increase of astrocytic production and release of the inhibitory neurotransmitter GABA after social deprivation. Collectively, our studies reveal how astrocyte function is tuned to social experience and identifies a social-context-specific mechanism by which astrocytic TRPA1 and GABA coordinately suppress hippocampal circuit function.
Topics: Mice; Animals; Astrocytes; Hippocampus; Neurons; Social Deprivation; gamma-Aminobutyric Acid; TRPA1 Cation Channel
PubMed: 36787749
DOI: 10.1016/j.neuron.2023.01.015