mGlu3 receptor regulates microglial cell reactivity in neonatal rats (original) (raw)
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Glutamate Receptors in Microglia
CNS & Neurological Disorders - Drug Targets, 2013
Expression of functional glutamate receptors (GluR) on glial cells in the developing and mature brain has been recently established. Over the last decade there has been physiological, molecular and biochemical evidence suggesting the presence of GluR on microglia. However, the significance of GluR activation in microglia remains largely unknown. In this review, we discuss the expression of GluR on microglia and the effect of GluR activation on microglial function. Microglia are the resident immune cells of the central nervous system, and activation of GluR in them has been shown to regulate their immunological response which may be either neuroprotective or neurotoxic. Microglial activation is known to initiate a myriad of molecular events such as nitric oxide production, free radicals generation, disruption of calcium regulation and release of proinflammatory cytokines, proteases, neurotransmitters, and excitatory amino acids, primarily glutamate. Since microglial activation has been implicated in several neuropathologies, an understanding of the pathway coupled to the various microglial GluR will help to develop therapeutic interventions for ameliorating microglia-mediated damage.
Frontiers in Neurology, 2021
Backgroud: Type-3 metabotropic glutamate (mGlu3) receptors are found in both neurons and glial cells and regulate synaptic transmission, astrocyte function, and microglial reactivity. Here we show that the genetic deletion of mGlu3 receptors amplifies ischemic brain damage and associated neuroinflammation in adult mice. An increased infarct size was observed in mGlu3−/− mice of both CD1 and C57Black strains 24 h following a permanent occlusion of the middle cerebral artery (MCA) as compared to their respective wild-type (mGlu3+/+ mice) counterparts. Increases in the expression of selected pro-inflammatory genes including those encoding interleukin-1β, type-2 cycloxygenase, tumor necrosis factor-α, CD86, and interleukin-6 were more prominent in the peri-infarct region of mGlu3−/− mice. In contrast, the expression of two genes associated with the anti-inflammatory phenotype of microglia (those encoding the mannose-1-phosphate receptor and the α-subunit of interleukin-4 receptor) and t...
Journal of Neuroscience Research, 2002
Recent studies confirm that astrocytes and neurons are associated with the synaptic transmission, particularly with the regulation of glutamate (Glu) levels. Therefore, they have the capacity to modulate the Glu released from neurons into the extracellular space. It has also been demonstrated an intense astrocytic and microglia response to physical or chemical lesions of the central nervous system. However, the persistence of the response of the glial cells in adult brain had not been previously reported, after the excitotoxic damage caused by neonatal dosage of monosodium glutamate (MSG) to newborn rats. In this study, 4 mg/g body weight of MSG were administered to newborn rats at 1, 3, 5, and 7 days after birth, at the age of 60 days the astrocytes and the microglia cells were analyzed with immunohistochemical methods in the fronto-parietal cortex. Double labeling to glial fibrillary acidic protein (GFAP) and BrdU, or isolectin-B4 and BrdU identified astrocytes or microglia cells that proliferated; immunoblotting and immunoreactivity to vimentin served for assess immaturity of astrocytic intermediate filaments. The results show that the neonatal administration of MSG-induced reactivity of astrocytes and microglia cells in the fronto-parietal cortex, which was characterized by hyperplasia; an increased number of astrocytes and microglia cells that proliferated, hypertrophy; increased complexity of the cytoplasm extension of both glial cells and expression of RNAm to vimentin, with the presence of vimentin-positive astrocytes. This glial response to neuroexcitotoxic stimulus of Glu on the immature brain, which persisted to adulthood, suggests that the neurotransmitter Glu could trigger neuro-degenerative illnesses. © 2002 Wiley-Liss, Inc.
Prenatal Activation of Microglia Induces Delayed Impairment of Glutamatergic Synaptic Function
PLoS ONE, 2008
Background: Epidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established. Methodology/Principal Findings: In this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12 KI mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12 KI P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12 KI microglia overexpress genes for IL1b, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity. Conclusion/Significance: Our results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation.
Glia, 2009
The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. Using immunocytochemistry and Western blot, we demonstrate that mGluR5 protein is expressed in primary microglial cultures. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly reduces microglial activation in response to lipopolysaccharide, as indicated by a reduction in nitric oxide, reactive oxygen species, and TNFα production. Microglial induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the Gαq-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders. © 2008 Wiley-Liss, Inc.
Microglia toxicity in preterm brain injury
Reproductive Toxicology, 2014
Microglia are the resident phagocytic cells of the central nervous system. During brain development they are also imperative for apoptosis of excessive neurons, synaptic pruning, phagocytosis of debris and maintaining brain homeostasis. Brain damage results in a fast and dynamic microglia reaction, which can influence the extent and distribution of subsequent neuronal dysfunction. As a consequence, microglia responses can promote tissue protection and repair following brain injury, or become detrimental for the tissue integrity and functionality. In this review, we will describe microglia responses in the human developing brain in association with injury, with particular focus on the preterm infant. We also explore microglia responses and mechanisms of microglia toxicity in animal models of preterm white matter injury and in vitro primary microglia cell culture experiments.
Neuroscience, 2003
Previous studies in a mouse model of neonatal excitotoxic brain damage mimicking the brain lesions in human cerebral palsy showed microglial activation within 24 h after intracerebral injection of the glutamatergic analog ibotenate. Using this model, we studied the expression of CD-45 antigen, a marker of blood-derived cells, by these activated microglial cells labeled by Griffonia simplicifolia I isolectin B4. Immunohistochemistry performed during early development of excitotoxic lesions showed that most cells labeled with the isolectin B4 were CD-45-negative, suggesting that these early activated microglial cells were deriving chiefly from resident microglia and not from circulating monocytes. We also directly tested the hypothesis that activated resident microglia and/or blood-derived monocytes play a role in the pathophysiology of excitotoxic brain damage. Repeated i.p. administrations of chloroquine, chloroquine؉colchicine, minocycline, or an anti-MAC1 antibody coupled to the toxin saporin before and/or after ibotenate injection induced a significant reduction in the density of isolectin B4-positive cells. This inhibition of resident microglial and/or blood-derived monocytes activation was accompanied by a significant reduction in the severity of ibotenate-induced brain lesions (up to 79% lesion size reduction with the highest minocycline dose) as well as of ibotenate-induced cortical caspase-3 activation (49% reduction).
Glia, 2005
This study investigates the effect of microglial activation on microglial glutamate transporters in vitro. Stimuli known to activate microglia and=or to be associated with pathological conditions with an impaired astroglial glutamate uptake were compared. Morphological changes and marked increases in ED1 antigen expression were found after 8-h incubation of rat microglia in 56 mM KCl, 1 ng=ml lipopolysaccharide (LPS), and 100 mM glutamate, as well as in acidic and basic conditions, showing that the cells were activated. Of the stimuli used, only LPS induced a significant release of the proinflammatory cytokines tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), and was the only stimulus that increased microglial GLT-1 expression and glutamate uptake capacity after 12-h incubation. This effect was probably mediated by TNF-a, since this cytokine mimicked the effect of LPS. Furthermore, the effect of LPS was blocked by thalidomide, an inhibitor of TNF-a synthesis. Additionally, neutralizing antibodies against TNF-a also blocked the increase, indicating TNF-a as an inducer of GLT-1 expression in microglia. It was also found that preincubation with glutamate dose-dependently inhibited the microglial glutamate uptake. This could suggest different physiological functions for microglial and astroglial glutamate uptake and might indicate a reciprocal control of GLT-1 expression between microglia and astrocytes.