Activity-dependent modulation of synapse-regulating genes in astrocytes
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ABSTRACT:
PROVIDER: PRJNA687513 | ENA |
REPOSITORIES: ENA
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| S-EPMC8497060 | biostudies-literature
Project description:Analysis of astrocyte heterogeneity in the developing mouse visual cortex, and identification of genes regulated by neuronal and astrocyte activity
2021-10-07 | GSE163775 | GEO
Project description:Synapse loss and glial activation are hallmarks of Alzheimer's disease (AD). In Tau P301S transgenic mice, the complement pathway contributes to neuronal damage through microglial elimination of synapses. Here, we used unbiased proteomic profiling of postsynaptic density (PSD) fractions from Tau P301S mice in C1q-WT versus C1q knockout backgrounds to identify C1q-dependent changes at synapses. Integrative multi-omics analysis revealed that astrocyte- and microglia- specific proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. The same set of glial proteins (including C1q, C4, Gpnmb, and S100a4) is elevated in human AD synaptic fractions, and C4 levels are raised in cerebrospinal fluid (CSF) from AD patients. Besides microglia, we show that astrocytes contribute substantially to excitatory and inhibitory synapse engulfment in Tau P301S hippocampus. Based on staining of synapse markers within lysosomes, astrocytes showed preference for excitatory synapses whereas microglia preferred to engulf inhibitory synapse markers. Genetic deletion of C1q reduced astrocytic eating of excitatory and inhibitory synapses in Tau P301S mice, and rescued synapse density. Together, our data indicate that astrocytes contact and phagocytose synapses in a C1q- dependent manner and thereby contribute to synapse loss and neurodegeneration in AD.
2021-11-03 | MSV000088313 | MassIVE
Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.
2022-03-17 | GSE185052 | GEO
Project description:Astrocytes regulate the functional maturation of neurons by providing trophic support, regulating membrane properties and coordinating synapse formation. However, it is unclear to what degree astrocytes use activity-dependent mechanisms in these intercellular signalling processes. Using an induced pluripotent stem cell system and long-term optogenetic stimulation of human astrocytes, we reveal that activity-dependent astrocytic signals enhance the functional maturation of human cortical neurons, through increases in synaptic connectivity and excitability. Transcriptomic analyses determine that this involves the activity-dependent up-regulation of cholesterol synthesis – a process ascribed to astrocytes, which regulates neuronal maturation. Up-regulated astrocyte genes encode enzymes and transcription factors that control the levels of cholesterol synthesis. Biochemical assays confirm an activity-dependent upregulation of cholesterol synthesis in astrocytes, which is required for the maturational effects upon neurons. Thus, we reveal a novel mechanism that may dynamically match astrocyte function to neuronal needs, and identify targets for modulating cholesterol synthesis in the CNS.
2023-07-21 | GSE236398 | GEO
Project description:Protein coding gene expression requires two steps – transcription and translation – which can be regulated independently to allow nuanced, localized, and rapid responses to cellular stimuli. Neurons are known to respond transcriptionally and translationally to bursts of brain activity, and a transcriptional response to this activation has also been recently characterized in astrocytes. However, the extent to which astrocytes respond translationally is unknown. We tested the hypothesis that astrocytes also have a programmed translational response by characterizing the change in transcript ribosome occupancy in astrocytes using Translating Ribosome Affinity Purification subsequent to a robust induction of neuronal activity in vivo via acute seizure. We identified a reproducible change in transcripts on astrocyte ribosomes, highlighted by a rapid decrease in housekeeping transcripts, such as ribosomal and mitochondrial components, and a rapid increase in transcripts related to cytoskeleton, motor activity, ion transport, and cell communication. This indicates a dynamic response, some of which might be secondary to activation of Receptor Tyrosine Kinase signaling. Using acute slices, we quantified the extent to which individual cues and sequela of neuronal activity can activate translation acutely in astrocytes. This identified both BDNF and KCl as contributors to translation induction, the latter with both action-potential sensitive and insensitive components. Finally, we show that this translational response requires the presence of neurons, indicating the response is acutely or chronically non-cell autonomous. Regulation of translation in astrocytes by neuronal activity suggests an additional mechanism by which astrocytes may dynamically modulate nervous system functioning.
2022-11-17 | GSE147830 | GEO
Project description:Early life stress such as childhood abues and childhood neglect has been frequently implicated in evoking mental disorders later in life. However, it is not well understood what is the underlying mechanism between early life stress and mental disorders. Our in vitro, in vivo and brain organoid experiments revealed that stress hormones increase Mertk expression in astrocytes through glucocorticoid receptor (GR). Furthermore, early life stress (ESD) exposure significantly incrased astrocyte-mediated synapse phagocytosis via GR/MERTK pathway in various brain regions including somatosensory cortex and orbitofrontal cortex. In those brain regions, the excitatory postsynaptic density was remarkably decreased with an increase in astrocytic phagocytosis of excitatory postsynapses. Importantly, ablating GR or MERTK in astrocytes prevented ESD-induced loss of excitatory snapses, abnormal neural activities and behavioral deficits. Taken together, this study revelas a new role of astrocytic GR/MERTK pathway in evoking stress-induced abnormal behaviors in mice, suggesting astrocytic GR/MERTK signaling could be a potential therapeutic target for stress-induced mental disorders.
2023-08-22 | GSE234945 | GEO
Project description:In this study we analyzed the contribution of PHF8 histone demethylase to astrocytes differentiation from mouse neural stem cells. We found that PHF8 depletion affects astocytes differentiation. Moreover, PHF8 is crucial for synaptogenesis in neurons/astrocytes cocultures. Genome wide analysis demonstrated that PHF8 controls the expression of critical astrogenic and synaptogenic genes by keeping low levels of H4K20me1 at promoters. PHF8 depletion induces aberrant astrocytes phenotype and caused a significant decrease in miniature excitatory postsynaptic currents (mEPSC) frequency and amplitude in neurons/astrocytes coclutures. These data reveal a new role of PHF8 in astrocyte differentiation and function, modulating neuronal synapse. Thus, lack of histone demethylase activity associated to PHF8 mutations might led to synapse disfunction that could directly impact into X-linked intellectual disabilities.
2021-06-14 | GSE141970 | GEO
Project description:Neuronal synapse formation and remodeling is essential to central nervous system (CNS) development and is dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this impacts CNS synapses is largely unknown. Here we show that the IL-1 family cytokine Interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development.
2018-02-05 | GSE109353 | GEO
Project description:Neuronal synapse formation and remodeling is essential to central nervous system (CNS) development and is dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this impacts CNS synapses is largely unknown. Here we show that the IL-1 family cytokine Interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development.
2018-02-05 | GSE109352 | GEO