-
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 -
Trends in Molecular Medicine Feb 2019Astrocytic contributions to Alzheimer's disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte... (Review)
Review
Astrocytic contributions to Alzheimer's disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early feature of AD, potentially providing a promising target for preclinical diagnosis and treatment. Several in vivo AD biomarkers already exist, but presently there is a paucity of specific and sensitive in vivo astrocyte biomarkers that can accurately measure preclinical AD. Measuring monoamine oxidase-B with neuroimaging and glial fibrillary acidic protein from bodily fluids are biomarkers that are currently available. Developing novel, more specific, and sensitive astrocyte biomarkers will make it possible to pharmaceutically target chemical pathways that preserve beneficial astrocytic functions in response to AD pathology. This review discusses astrocyte biomarkers in the context of AD.
Topics: Alzheimer Disease; Animals; Astrocytes; Biomarkers; Glucose; Humans
PubMed: 30611668
DOI: 10.1016/j.molmed.2018.11.006 -
CNS Neuroscience & Therapeutics Jun 2019Astrocytes are the most abundant glial cells in the central nervous system (CNS) and participate in synaptic, circuit, and behavioral functions. The well-developed... (Review)
Review
Astrocytes are the most abundant glial cells in the central nervous system (CNS) and participate in synaptic, circuit, and behavioral functions. The well-developed protoplasmic astrocytes contain numerous processes forming well-delineated bushy territories that overlap by as little as 5% at their boundaries. This highly complex morphology, with up to approximately 80% of the cell's membrane constituted by fine processes with dimensions on the tens of nanometer scale and high surface area to volume ratios, comes in contact with synapses, blood vessels, and other glial cells. Recent progress is challenging the conventional view that astrocytes are morphologically homogeneous throughout the brain; instead, they display circuit- and region-specific morphological diversity that may contribute to the heterogeneous astrocyte-neuron spatiotemporal interplay in different brain areas. Further, the fine structure of astrocytes is found to be highly plastic and activity-dependent. We are beginning to understand how astrocyte structural plasticity contributes to brain functions. The change/loss of astrocyte morphology, traditionally known as a hallmark for reactive astrogliosis, is a common pathological feature in many neurological disorders. However, recent data suggest the fine structural deficits preceding reactive astrogliosis may drive disease progression. This review summarizes recent advances in astrocyte morphological diversity, plasticity, and disease-related deficits.
Topics: Animals; Astrocytes; Brain; Humans; Neurodegenerative Diseases; Neuronal Plasticity
PubMed: 30929313
DOI: 10.1111/cns.13123 -
Glia Aug 2015Astrocytes are the predominant cell type in the brain and perform key functions vital to CNS physiology, including blood brain barrier formation and maintenance,... (Review)
Review
Astrocytes are the predominant cell type in the brain and perform key functions vital to CNS physiology, including blood brain barrier formation and maintenance, synaptogenesis, neurotransmission, and metabolic regulation. To fully understand the contributions of astrocytes to brain function, it will be important to bridge the existing gap between development and physiology. In this review, we provide an overview of Astrocyte development, including recent insights into molecular mechanisms of astrocyte specification, regional patterning and proliferation. This developmental perspective is complemented with recent findings that describe the functional maturation of astrocytes and their prospective diversity. Future progress in understanding Astrocyte development will depend on the development of astrocyte- stage specific markers and tools for manipulating astrocytes without affecting neuron production. Ultimately, a mechanistic approach to Astrocyte development will be crucial to developing new treatments for the many neurodevelopmental, neurodegenerative, neuroimmune, and neoplastic diseases involving astrocyte dysfunction.
Topics: Animals; Astrocytes; Cell Proliferation; Humans; Neural Stem Cells
PubMed: 25963996
DOI: 10.1002/glia.22836 -
The Journal of Physiology Mar 2017Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently... (Review)
Review
Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder, schizophrenia, and Alzheimer's disease. In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathologies. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.
Topics: Animals; Astrocytes; Dendritic Spines; Humans; Nervous System Diseases; Neurodevelopmental Disorders; Synapses
PubMed: 27381164
DOI: 10.1113/JP270988 -
Nature May 2023Communication between neurons and glia has an important role in establishing and maintaining higher-order brain function. Astrocytes are endowed with complex...
Communication between neurons and glia has an important role in establishing and maintaining higher-order brain function. Astrocytes are endowed with complex morphologies, placing their peripheral processes in close proximity to neuronal synapses and directly contributing to their regulation of brain circuits. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unclear. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABA receptor (GABAR) and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABAR in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together, our studies identify input from inhibitory neurons and astrocytic GABAR as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes.
Topics: Astrocytes; gamma-Aminobutyric Acid; Neurons; Synapses; Cell Shape; Receptors, GABA-B; SOX9 Transcription Factor; NFI Transcription Factors; Gene Expression Regulation; Neural Inhibition
PubMed: 37100909
DOI: 10.1038/s41586-023-06010-x -
Nature Nov 2017Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the...
Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology.
Topics: Animals; Astrocytes; Cell Adhesion Molecules, Neuronal; Cell Shape; Cerebral Cortex; Mice; Neural Cell Adhesion Molecules; Neural Inhibition; Receptors, Cell Surface; Synapses
PubMed: 29120426
DOI: 10.1038/nature24638 -
Neurochemistry International Dec 2019The understanding of the physiology of astrocytes and their role in brain function progresses continuously. Primary astrocyte culture is an alternative method to study...
The understanding of the physiology of astrocytes and their role in brain function progresses continuously. Primary astrocyte culture is an alternative method to study these cells in an isolated system: in their physiologic and pathologic states. Cell lines are often used as an astrocyte model, since they are easier and faster to manipulate and cost less. However, there are a few studies evaluating the different features of these cells which may put into question the validity of using them as astrocyte models. The aim of this study was to compare primary cultures (PC) with two cell lines - immortalized astrocytes and C6 cells, in terms of protein characterization, morphology and metabolic functional activity. Our results showed, under the same culture condition, that immortalized astrocytes and C6 are positive for differentiated astrocytic markers (eg. GFAP, S100B, AQP4 and ALDH1L1), although expressing them in less quantities then primary astrocyte cultures. Glutamate metabolism and cell communication are reduced in proliferative cells. However, glucose uptake is elevated in C6 lineage cells in comparison with primary astrocytes, probably due to their tumorigenic origin and high proliferation rate. Immortalized astrocytes presented a lower growth rate than C6 cells, and a similar basal morphology as primary astrocytes. However, they did not prove to be as good reproductive models of some of the classic astrocytic functions, such as S100B secretion and GFAP content, especially while under stimulation. In contrast, C6 cells presented similar results in comparison to primary astrocytes in response to stimuli. Here we provide a functional comparison of three astrocytic models, in an attempt to select the most suitable model for the study of astrocytes, optimizing the research in this area of knowledge.
Topics: Animals; Astrocytes; Brain Neoplasms; Cell Communication; Cell Line; Cell Proliferation; Glial Fibrillary Acidic Protein; Glioma; Glucose; Glutamic Acid; Glutathione; Immunohistochemistry; Male; Primary Cell Culture; Rats; Rats, Wistar; S100 Calcium Binding Protein beta Subunit
PubMed: 31430518
DOI: 10.1016/j.neuint.2019.104538 -
Progress in Neurobiology Jun 2022The complexity of astrocyte morphology and syncytial coupling through gap junctions are crucial for astrocyte function in the brain. However, the ultrastructural details...
The complexity of astrocyte morphology and syncytial coupling through gap junctions are crucial for astrocyte function in the brain. However, the ultrastructural details of astrocyte arborization and interactions between neighboring astrocytes remain unknown. While a prevailing view is that synapses selectively contact peripheral astrocyte processes, the precise spatial-location selectivity of synapses abutting astrocytes is unresolved. Additionally, knowing the location and quantity of vesicles and mitochondria are prerequisites to answer two emerging questions - whether astrocytes have a signaling role within the brain and whether astrocytes are highly metabolically active. Here, we provided structural context for these questions by tracing and 3D reconstructing three neighboring astrocytes using serial block-face scanning electron microscopy. Our reconstructions reveal a spongiform astrocytic morphology resulting from the abundance of reflexive and leaflet processes. At the interfaces, varying sizes of astrocyte-astrocyte contacts were identified. Inside an astrocyte domain, synapses contact the entire astrocyte, and synapse-astrocyte contacts increase from soma to terminal leaflets. In contrast to densely packed vesicles at synaptic boutons, vesicle-like structures were scant within astrocytes. Lastly, astrocytes contain dense mitochondrial networks with a mitochondrial volume ratio similar to that of neurites. Together, these ultrastructural details should expand our understanding of functional astrocyte-astrocyte and astrocyte-neuron interactions.
Topics: Astrocytes; Brain; Humans; Mitochondria; Neurons; Synapses
PubMed: 35283239
DOI: 10.1016/j.pneurobio.2022.102264 -
Aging Cell Jun 2019Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles... (Review)
Review
Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles can therefore be a contributor to CNS dysfunction and pathology. Cellular senescence, one of the mechanisms of aging, has been proposed as a central component of the age dependency of neurodegenerative disorders. Cumulative evidence supports an integral role of astrocytes in the initiation and progression of neurodegenerative disease and cognitive decline with aging. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term "astrosenescence" to describe this phenotype. This review summarizes the current evidence pertaining to astrocyte senescence from early evidence, in vitro characterization and relationship to age-related neurodegenerative disease. We discuss the significance of targeting senescent astrocytes as a novel approach toward therapies for age-associated neurodegenerative disease.
Topics: Astrocytes; Cellular Senescence; Humans; Neurodegenerative Diseases
PubMed: 30815970
DOI: 10.1111/acel.12937