Negative feedback control of neuronal activity by microglia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA630448 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11688459.fastq.gz | Fastqsanger.gz | |||
| SRR11688460.fastq.gz | Fastqsanger.gz | |||
| SRR11688461.fastq.gz | Fastqsanger.gz | |||
| SRR11688462.fastq.gz | Fastqsanger.gz | |||
| SRR11688463.fastq.gz | Fastqsanger.gz |
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2020-08-18 | GSE149897 | GEO
Project description:Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
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Project description:The rapid elimination of dying neurons and non-functional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene expression programs supporting clearance activity. We provide evidence that the Polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 led to the aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.
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Project description:Phagocytosis of synaptic debris by microglia is critical for CNS development and homeostasis. Less well understood are microglial functions in injured adult brain, where their presumed role is clearance of neuronal debris. Assay of this process is challenging, because the resulting peripheral myeloid-cell engraftment is difficult to dissociate from microglial clearance. The model used here, optic nerve crush injury in adult mouse, stimulates rapid engulfment of synaptic material by microglia residing in the lateral geniculate nucleus (LGN), sufficiently distant from the injury to preclude peripheral-cell engraftment. Pre-injury pharmacological depletion of microglia causes post-injury accumulation of synaptic debris, suggesting that these, not astrocytes, are the dominant post-injury phagocytes. Genetic and pharmacological manipulations revealed that neuronal activity, which regulates microglial engulfment of synaptic debris in development, does not do so in post-injury synaptic material clearance in adulthood, where such clearance depends instead on axonal integrity. RNAseq reveals C1q involvement in clearance of debris by LGN-resident microglia, supporting our finding of its impaired clearance in C1qa-/- and Itgam-/- mice. Our results demonstrate how neurodegenerative debris is cleared by microglial phagocytosis, and offer a model for assaying microglial phagocytic activity and studying its mechanisms and physiological roles.
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Project description:T cell activation must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells, while avoiding autoimmunity. Our knowledge of the mechanisms controlling the fine-tuning of T cell receptor (TCR) signaling and T cell activation is still incomplete. The Syk family kinase ζ chain–associated protein kinase of 70 kD (ZAP-70) plays a critical role as part of the TCR signaling machinery that leads to T cell activation. To elucidate potential feedback targets that are dependent on the kinase activity of ZAP-70, we performed a mass spectrometry–based phosphoproteomic study to quantify temporal changes in phosphorylation patterns after inhibition of ZAP-70 catalytic activity. Our results provide insights into the fine-tuning of the T cell signaling network before as well as after TCR engagement. The data indicate that the kinase activity of ZAP-70 stimulates negative feedback pathways that target the Src family kinase Lck and modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ζ-chains, as well as of downstream signaling molecules, including ZAP-70 itself. We developed a computational model that provides a unified mechanistic explanation for the experimental data on ITAM phosphorylation in wild-type cells, ZAP-70-deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model describes the requirements of the ZAP-70 kinase–dependent negative feedback that influences Lck activation, and makes specific predictions for the order in which tyrosines in the ITAMs of TCR ζ-chains must be phosphorylated to be consistent with the experimental data.
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