Taylor, D.L.;
Diemel, L.T.;
Pocock, J.M.;
(2003)
Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity.
The Journal of Neuroscience
, 23
(6)
pp. 2150-2160.
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Abstract
A reduction in microglial activation and subsequent neurotoxicity may prove critical for neuroprotection in neurodegenerative diseases. We examined the expression and functionality of group III metabotropic glutamate (mGlu) receptors on microglia. Rat microglia express mRNA and receptor protein for group III mGlu receptors mGlu4, mGlu6, and mGlu8 but not mGlu7. Activation of these receptors on microglia with the specific group III agonists (L)-2-amino-4-phosphono-butyric acid (L-AP-4) or (R,S)-phosphonophenylglycine (RS-PPG) inhibited forskolin-induced cAMP production, linking these receptors to the negative inhibition of adenylate cyclase. These agonists did not induce a fall in mitochondrial membrane potential or apoptosis in the microglia, suggesting that activation of these receptors is not in itself toxic to microglia. Fluorescence-activated cell sorting analysis revealed that activation of group III mGlu receptors induces a mild activation of the microglia, as evidence by their enhanced staining with ED1. However, this activation is not neurotoxic. Agonists of group III mGlu receptors reduced microglial reactivity when they were activated with lipopolysaccharide (LPS), chromogranin A (CGA) or amyloid beta peptide 25-35 (Abeta 25-35). Furthermore, L-AP-4 or RS-PPG treatment of microglia reduced their neurotoxicity after microglial stimulation with LPS or CGA but not Abeta 25-35. Similar results were obtained with microglial conditioned medium or in coculture, suggesting that the activation of microglial group III mGlu receptors may modulate the production of stable neurotoxins from the microglia. These results suggest that selective modulation of microglial group III mGlu receptors may provide a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease.
| Type: | Article |
|---|---|
| Title: | Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity |
| Open access status: | An open access version is available from UCL Discovery |
| Publisher version: | http://www.jneurosci.org/cgi/content/abstract/23/6... |
| Language: | English |
| Additional information: | Copyright the Society for Neuroscience 2003. This work is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. The license allows you to copy, distribute, and transmit the work, as well as adapting it. However, you must attribute the work to the author (but not in any way that suggests that they endorse you or your use of the work), and cannot use the work for commercial purposes without prior permission of the author. If you alter or build upon this work, you can distribute the resulting work only under the same or similar license to this one. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA. |
| Keywords: | Neurodegenerative disease, Alzheimer's disease, microglia, neurotoxicity, metabotropic glutamate receptors, neuroprotection |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neuroinflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/7724 |
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