Activation of Microglial Group III Metabotropic Glutamate Receptors Protects Neurons against Microglial Neurotoxicity

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 ␤ peptide 25-35 (A␤25-35). Furthermore, L-AP-4 or RS-PPG treatment of microglia reduced their neurotoxicity after microglial stimulation with LPS or CGA but not A␤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.

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

“…In primary monocultures and microglia-neuron cultures, LPS exposure alone or in combination with IFN-γ for a "booster" triggers the massive release of proinflammatory and cytotoxic factors, such as TNF-α, IL-6, and nitric oxide (NO), finally resulting in neuronal death (8,(11)(12)(13)(14)(15)(16)(17)(18). Similar effects were observed in vivo after intracerebral administration of LPS (19)(20)(21).…”

Primary Neuron/Astrocyte Co‐Culture on Polyelectrolyte Multilayer Films: A Template for Studying Astrocyte‐Mediated Oxidative Stress in Neurons

“…Thus the ability to create and maintain neuronal and astrocyte co-cultures are crucial in developing neuronal systems to study neuron function and interactions between neurons and glial cells. [1,4,24] Different approaches have been used to create spatially defined co-cultures of two different cell types. [25,26] However, these techniques have certain limitations.…”

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

“…The process is blocked by the administration of (+)-α-methyl-4-carboxyphenylglycine, a non-selective antagonist of group I/II mGluRs [228]. Activation of group III mGluRs has also been shown to protect neurons against microglial neurotoxicity during Aβ application [218] that may be a result of the regulation of caspase activity [43,124]. Under some circumstances, diminished activity of mGluRs may prove useful for cellular protection.…”

“…Under some circumstances, diminished activity of mGluRs may prove useful for cellular protection. For example, inhibition of group II mGluRs can attenuate microglial activation and subsequent neurotoxicity during toxic stimuli such as chromogranin A [218], a protein up-regulated in Alzheimer's disease. mGluRs are also believed to be necessary for the processing of learning and memory [188].…”