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Negative feedback control of neuronal activity by microglia.

ABSTRACT: 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.

SUBMITTER: Badimon A

PROVIDER: S-EPMC7577179 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Negative feedback control of neuronal activity by microglia

Project description:Microglia, the brain resident macrophages, play a key role in the regulation of brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. We have identified a new function of microglia as critical modulators of neuronal activity and associated behavioral responses in mice. We show that microglia respond to neuronal activation and that ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. The suppressive impact of microglia on neuronal activation occurs in a highly localized fashion and depends on the ability of microglia to sense and catabolize extracellular ATP. ATP, which can be released upon neuronal activation by neurons and astrocytes, triggers the recruitment of microglia protrusions and is converted by the microglial ATP-hydrolyzing enzyme CD39 and CD73 into AMP and adenosine, a potent suppressor of neuronal activity. We show that the microglial sensing of ATP, the ensuing production of adenosine, and the adenosine-mediated control of neuronal response via the A1R are essential for the microglia-mediated regulation of neuronal activity and animal behavior. Our findings suggest that this microglia-driven negative feedback mechanism operates in a fashion similar to inhibitory neurons and plays an essential role in protecting the brain from excessive activation in health and diseases.

2020-08-18 | GSE149897 | GEO

Negative feedback control of neuronal activity by microglia

Project description:Negative feedback control of neuronal activity by microglia

| PRJNA630448 | ENA

MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision.

Project description:The elucidation of the architecture of gene regulatory networks that control cell-type specific gene expression programs represents a major challenge in developmental biology. We describe here a cell fate decision between two alternative neuronal fates and the architecture of a gene regulatory network that controls this cell fate decision. The two Caenorhabditis elegans taste receptor neurons "ASE left" (ASEL) and "ASE right" (ASER) share many bilaterally symmetric features, but each cell expresses a distinct set of chemoreceptors that endow the gustatory system with the capacity to sense and discriminate specific environmental inputs. We show that these left/right asymmetric fates develop from a precursor state in which both ASE neurons express equivalent features. This hybrid precursor state is unstable and transitions into the stable ASEL or ASER terminal end state. Although this transition is spatially stereotyped in wild-type animals, mutant analysis reveals that each cell has the potential to transition into either the ASEL or ASER stable end state. The stability and irreversibility of the terminal differentiated state is ensured by the interactions of two microRNAs (miRNAs) and their transcription factor targets in a double-negative feedback loop. Simple feedback loops are found as common motifs in many gene regulatory networks, but the loop described here is unusually complex and involves miRNAs. The interaction of miRNAs in double-negative feedback loops may not only be a means for miRNAs to regulate their own expression but may also represent a general paradigm for how terminal cell fates are selected and stabilized.

| S-EPMC1194938 | biostudies-literature

A PI3-kinase-mediated negative feedback regulates neuronal excitability.

Project description:Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

| S-EPMC2581892 | biostudies-literature

Polysialic acid and Siglec-E orchestrate negative feedback regulation of microglia activation.

Project description:Polysialic acid (polySia) emerges as a novel regulator of microglia activity. We recently identified polysialylated proteins in the Golgi compartment of murine microglia that are released in response to inflammatory stimulation. Since exogenously added polySia is able to attenuate the inflammatory response, we proposed that the release of polysialylated proteins constitutes a mechanism for negative feedback regulation of microglia activation. Here, we demonstrate that translocation of polySia from the Golgi to the cell surface can be induced by calcium depletion of the Golgi compartment and that polysialylated proteins are continuously released for at least 24 h after the onset of inflammatory stimulation. The latter was unexpected, because polySia signals detected by immunocytochemistry are rapidly depleted. However, it indicates that the amount of released polySia is much higher than anticipated based on immunostaining. This may be crucial for microglial responses during traumatic brain injury (TBI), as we detected polySia signals in activated microglia around a stab wound in the adult mouse brain. In BV2 microglia, the putative polySia receptor Siglec-E is internalized during lipopolysaccharide (LPS)-induced activation and in response to polySia exposure, indicating interaction. Correspondingly, CRISPR/Cas9-mediated Siglec-E knockout prevents inhibition of pro inflammatory activation by exogenously added polySia and leads to a strong increase of the LPS response. A comparable increase of LPS-induced activation has been observed in microglia with abolished polySia synthesis. Together, these results indicate that the release of the microglia-intrinsic polySia pool, as implicated in TBI, inhibits the inflammatory response by acting as a trans-activating ligand of Siglec-E.

| S-EPMC7904730 | biostudies-literature

Control and regulation of pathways via negative feedback.

Project description:The biochemical networks found in living organisms include a huge variety of control mechanisms at multiple levels of organization. While the mechanistic and molecular details of many of these control mechanisms are understood, their exact role in driving cellular behaviour is not. For example, yeast glycolysis has been studied for almost 80 years but it is only recently that we have come to understand the systemic role of the multitude of feedback and feed-forward controls that exist in this pathway. In this article, control theory is discussed as an approach to dissect the control logic of complex pathways. One of the key issues is distinguishing between the terms control and regulation and how these concepts are applied to regulated enzymes such as phosphofructokinase. In doing so, one of the paradoxes in metabolic regulation can be resolved where enzymes such as phosphofructokinase have little control but, nevertheless, possess significant regulatory influence.

| S-EPMC5332569 | biostudies-literature

MMAB promotes negative feedback control of cholesterol homeostasis.

Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.

| S-EPMC8575900 | biostudies-literature

NF-κB regulates neuronal ankyrin-G via a negative feedback loop.

Project description:The axon initial segment (AIS) is a neuronal compartment defined by ankyrin-G expression. We here demonstrate that the IKK-complex co-localizes and interacts with the cytoskeletal anchor protein ankyrin-G in immunoprecipitation and proximity-ligation experiments in cortical neurons. Overexpression of the 270 kDa variant of ankyrin-G suppressed, while gene-silencing of ankyrin-G expression increased nuclear factor-κB (NF-κB) activity in primary neurons, suggesting that ankyrin-G sequesters the transcription factor in the AIS. We also found that p65 bound to the ank3 (ankyrin-G) promoter sequence in chromatin immunoprecipitation analyses thereby increasing ank3 expression and ankyrin-G levels at the AIS. Gene-silencing of p65 or ankyrin-G overexpression suppressed ank3 reporter activity. Collectively these data demonstrate that p65/NF-κB controls ankyrin-G levels via a negative feedback loop, thereby linking NF-κB signaling with neuronal polarity and axonal plasticity.

| S-EPMC5299403 | biostudies-literature

Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion.

Project description:The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.

| S-EPMC4496282 | biostudies-literature

Negative BOLD with large increases in neuronal activity.

Project description:Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used in neuroscience to study brain activity. However, BOLD fMRI does not measure neuronal activity directly but depends on cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO(2)) consumption. Using fMRI, CBV, CBF, neuronal recordings, and CMRO(2) modeling, we investigated how the signals are related during seizures in rats. We found that increases in hemodynamic, neuronal, and metabolic activity were associated with positive BOLD signals in the cortex, but with negative BOLD signals in hippocampus. Our data show that negative BOLD signals do not necessarily imply decreased neuronal activity or CBF, but can result from increased neuronal activity, depending on the interplay between hemodynamics and metabolism. Caution should be used in interpreting fMRI signals because the relationship between neuronal activity and BOLD signals may depend on brain region and state and can be different during normal and pathological conditions.

| S-EPMC2790390 | biostudies-literature

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