Activation of microglial N‐methyl‐D‐aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain

Kaindl, Angela M.; Degos, Vincent; Peineau, Stéphane; Gouadon, Elodie; Chhor, Vibol; Loron, Gauthier; Charpentier, Tifenn Le; Josserand, Julien; Ali, Carine; Vivien, Denis; Collingridge, Graham L.; Lombet, Alain; Issa, Lina; Frydman, René; Loeffler, Jean Philippe; Kavelaars, Annemieke; Verney, Catherine; Mantz, Jean; Gressèns, Pierre

doi:10.1002/ana.23626

Cited by 203 publications

(121 citation statements)

References 62 publications

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“…The AMPA type of glutamate receptor has been shown to be present in cultured microglia (145,287), along with metabotropic glutamate receptors: mGluR5 (group I), mGluR2, mGluR3 (group II) and mGluR4, mGluR6, and mGluR8 (group III) (38, 238,259,399,400,401). There is evidence for the expression NMDA receptors on microglia also in the intact brain, although no in situ electrophysiological data have been given (181). Microglia in culture express metabotropic GABA B receptors (205), whereas microglial responses to GABA A receptor activation (284) are thought to be due to indirect effects (65).…”

Section: B Microglia Express Neurotransmitter Receptorsmentioning

confidence: 99%

Neuroglial Transmission

Gundersen

Storm‐Mathisen

Bergersen

2015

Physiological Reviews

155

113

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Neuroglia, the "glue" that fills the space between neurons in the central nervous system, takes active part in nerve cell signaling. Neuroglial cells, astroglia, oligodendroglia, and microglia, are together about as numerous as neurons in the brain as a whole, and in the cerebral cortex grey matter, but the proportion varies widely among brain regions. Glial volume, however, is less than one-fifth of the tissue volume in grey matter. When stimulated by neurons or other cells, neuroglial cells release gliotransmitters by exocytosis, similar to neurotransmitter release from nerve endings, or by carrier-mediated transport or channel flux through the plasma membrane. Gliotransmitters include the common neurotransmitters glutamate and GABA, the nonstandard amino acid d-serine, the high-energy phosphate ATP, and l-lactate. The latter molecule is a "buffer" between glycolytic and oxidative metabolism as well as a signaling substance recently shown to act on specific lactate receptors in the brain. Complementing neurotransmission at a synapse, neuroglial transmission often implies diffusion of the transmitter over a longer distance and concurs with the concept of volume transmission. Transmission from glia modulates synaptic neurotransmission based on energetic and other local conditions in a volume of tissue surrounding the individual synapse. Neuroglial transmission appears to contribute significantly to brain functions such as memory, as well as to prevalent neuropathologies.

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Section: B Microglia Express Neurotransmitter Receptorsmentioning

confidence: 99%

Neuroglial Transmission

Gundersen

Storm‐Mathisen

Bergersen

2015

Physiological Reviews

155

113

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“…Recent studies also show that microglia express NMDA receptors, and it is possible that these cells may react to high levels of extracellular glutamate, resulting in propagation of neuronal damage [229]. NMDA receptor stimulation triggers microglia activation and secretion of factors that induce cell death of cortical neurons, and in turn, damaged neurons activate microglial NMDA receptors to aggravate neurologic disease [230].…”

Section: Microgliamentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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“…A recent study even showed that ramified microglia plays an active protective role against NMDA induced excitotoxicity (Vinet et al, 2012). On the other hand, another study showed that microglia expresses functional NMDA receptors that upon activation may trigger secretion of factors leading to neuronal death (Kaindl et al, 2012). However, we were not able to distinguish their phenotype and role during NMDA induced neurodegeneration with immunohistochemistry.…”

Section: Neurodegeneration Was Accompanied With Progressive Neuroinflmentioning

confidence: 63%

Rat intra-hippocampal NMDA infusion induces cell-specific damage and changes in expression of NMDA and GABAA receptor subunits

et al. 2016

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Excessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABAA 5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABAA receptors. Highlights:1. The infusion of NMDA induced degeneration of hippocampal principal cells. 2. Neurodegeneration was accompanied with progressive and severe neuroinflammation. 3. The lesion did not induce loss of GABAergic interneurons. 4. GluN1 and GluN2B subunits of NMDA receptor were upregulated at early time points.5. GABA A receptor α5 subunit was downregulated at 30 days after the lesion. ABSTRACTExcessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABA A α5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABA A receptors.

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Activation of microglial N‐methyl‐D‐aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain

Abstract: Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain.

Cited by 203 publications

References 62 publications

Neuroglial Transmission

Neuroglial Transmission

Slow Excitotoxicity in Alzheimer's Disease

Rat intra-hippocampal NMDA infusion induces cell-specific damage and changes in expression of NMDA and GABAA receptor subunits

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