Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity.
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 (Abeta25-35). Furthermore, l-AP-4 or RS-PPG treatment of microglia reduced their neurotoxicity after microglial stimulation with LPS or CGA but not Abeta25-35. 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.
Taylor
Deanna L
DL
Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London, WC1N 1PJ, United Kingdom.
Diemel
Lara T
LT
Pocock
Jennifer M
JM
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D053379:Chromogranin A; D002864:Chromogranins / Q000494:pharmacology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005434:Flow Cytometry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000502:physiology
D016229:Amyloid beta-Peptides; D053379:Chromogranin A; D002864:Chromogranins; D017077:Culture Media, Conditioned; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C074636:amyloid beta-protein (25-35); C113897:metabotropic glutamate receptor 6; C111435:metabotropic glutamate receptor 8; C108823:metabotropic glutamate receptor 4