Myelin‐induced microglial neurotoxicity can be controlled by microglial metabotropic glutamate receptors

Abstract

Microglia are present in an activated state in multiple sclerosis lesions. Incubation of primary cultured rat microglia with rat‐brain derived myelin (0.1–1 μg/mL) for 24 h induced microglial activation; cells displayed enhanced ED1 staining, expression of inducible nitric oxide synthase, production and release of the cytokine tumour necrosis factor‐α and glutamate release. Exposure of microglia to myelin induced the expression of neuronal caspases and ultimately neuronal death in cultured cerebellar granule cell neurons; neurotoxicity was directly because of microglial‐derived soluble toxins. Co‐incubation of microglia with agonists or antagonists of different metabotropic glutamate receptor (mGluR) subtypes ameliorated microglial neurotoxicity by inhibiting soluble neurotoxin production. Activation of microglial mGluR2 exacerbated myelin‐evoked neurotoxicity whilst activation of mGluR3 was protective as was activation of group III mGluRs. These data show that myelin‐induced microglial neurotoxicity can be prevented by regulation of mGluRs and suggest these receptors on microglia may be promising targets for therapeutic intervention in multiple sclerosis.

Microglial Activation in Stroke: Therapeutic Targets

“…100 -104 They also express all three groups of metabotropic receptors: group I (mGluR5), 105 group II (mGluR2 and 3), 106,107 and group III (mGluR4, 6, and 8). 106,108 Stimulation with either glutamate or with ionotropic glutamate receptor agonists induces microglial proliferation, morphological changes characteristic of microglial activation, and release of IL-1␤, TNF␣, NO, and ATP.…”

“…100,101,104,109 Conversely, activation of most mGluR types inhibits microglial inflammatory responses, 107,110 -112 with the exception that mGluR2 activation promotes microglial neurotoxicity. 106,107 Microglia expression of glutamate receptor subtypes in vivo has not been extensively characterized, but protein expression of mGluR1, mGLuR2/3, and mGluR8 has been reported in microglia surrounding human multiple sclerosis lesions, 113 and expression of ionotropic glutamate receptors has been detected in reactive microglia in damaged areas of the hippocampus following ischemia. 114 The acute administration of an mGluR5 agonist after experimental stroke or spinal cord injury is neuroprotective, 115,116 and an mGluR5 agonist was also shown to reduce microglial activation in the spinal cord injury study, 116 suggesting that the neuroprotective effect of these agents may be attributable to the suppression of microglial activation.…”

The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis

“…12 Also, metabotropic glutamate (mGlu) receptors have been claimed to modulate excitotoxic neuronal damage, as group I mGlu receptors (mGlu 1 and 5) have a preferential synaptic localization and shape both AMPA 13,14 and NMDA signaling and toxicity, 15 whereas group II mGlu (mGlu 2 and 3) and group III mGlu receptors (mGlu 4,6,8) are preferentially located in presynaptic neuronal elements or in glial cells, where they can be both neuroprotective 15 or detrimental for neuronal survival. 16,17 Early studies have identified the neurotransmitter glutamate as an important determinant of neurodegenerative damage in the course of MS. 18,19 In fact, glutamate levels increase in the cerebrospinal fluid 20,21 and in the brains of MS patients, 18,19 whereas the AMPA, NMDA and kainate receptors are upregulated. 22 In addition, expressions of glutamate transporters are altered in MS [23][24][25] and in animal models of the disease, 26,27 and the loss of glutamate transporters in cortical lesions correlates with microglial activation and synaptic damage.…”

“…Activated microglial cells, in fact, are capable of releasing 57,58 and of metabolizing glutamate, 57,58 and in regulating the sensitivity of neuronal AMPA receptors to synaptically released glutamate. 57,58 In addition, stimulation of mGlu 2 receptors (which are upregulated in MS lesions 57,58 ) enhances microglia-dependent TNFa release and neurotoxicity, 16,17 whereas activation of microglial mGlu 3, 4 and 8 (also upregulated in MS lesions 57,58 ) has the opposite effect. 45 Finally, in white matter MS lesions, microglia/macrophage activity is essential to clear myelin debris, thus promoting remyelination.…”

Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes

“…Importantly, astrocytes provide neurotrophic support through mGluR-mediated release of growth factors (Bruno et al, 1998;Ciccarelli et al, 1999;Jean et al, 2008). On microglia, mGluRs likely participate in cell migration toward regions showing high glutamate release (Liu et al, 2009a) and modulate the inflammatory phenotype adopted upon activation (Byrnes et al, 2009b;Pinteaux-Jones et al, 2008;Taylor et al, 2003). As mGluR agonists were reported to influence glutamate handling and inflammatory responses in the central nervous system, mGluRs are commonly proposed as relevant targets to treat neurological diseases.…”