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Myelin-induced microglial neurotoxicity can be controlled by microglial metabotropic glutamate receptors |
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| Authors: | Pinteaux-Jones Fleur Sevastou Ioanna G Fry Victoria A H Heales Simon Baker David Pocock Jennifer M |
| Institution: | Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London, UK; Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK; Laboratory of Experimental Neuroinflammation, Department of Neuroinflammation, Institute of Neurology, University College London, London, UK |
| 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. |
| Keywords: | glutamate receptor microglia myelin neurotoxicity |
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