Positive allosteric modulation of metabotropic glutamate receptor 5 down-regulates fibrinogen-activated microglia providing neuronal protection
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Updated: May 28, 2026
Primary Microglia Isolation from Mixed Glial Cell Cultures of Neonatal Rat Brain Tissue
Published on: August 15, 2012
Thomas M Piers1, Simon J Heales, Jennifer M Pocock
1Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, London WC1N 1PJ, UK.
Abstract:
Microglial activation and blood brain barrier dysfunction are significant hallmarks in an array of neurodegenerative disorders. A leaky blood brain barrier potentially allows infiltration of blood-borne proteins into the CNS parenchyma, and previous studies have shown that the blood borne protein fibrinogen (FG) can activate microglia to produce a neurotoxic phenotype. Here we show that FG-mediated neurotoxicity and ERK1/2 phosphorylation in neuronal cultures is significantly attenuated by activation of metabotropic glutamate receptor 5 (mGluR5) but not mGluR2. Furthermore, FG-mediated microglial activation was down-regulated by direct mGluR5 activation on these cells but not by mGluR2, suggesting that targeting microglial mGluR5 provides neuronal protection against blood protein-triggered innate inflammatory responses.
Insights
Metabotropic glutamate receptor 5 (mGluR5) activation protects neurons from fibrinogen-induced neurotoxicity. Targeting microglial mGluR5 offers a potential strategy against neuroinflammation triggered by blood-borne proteins in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Neuroimmunology
- Neuropharmacology
Background:
- Microglial activation and blood-brain barrier (BBB) dysfunction are implicated in neurodegenerative disorders.
- Blood-borne proteins, such as fibrinogen (FG), can infiltrate the CNS and activate microglia, leading to a neurotoxic phenotype.
Purpose of the Study:
- To investigate the role of metabotropic glutamate receptor 5 (mGluR5) and mGluR2 in modulating fibrinogen-induced neurotoxicity and microglial activation.
- To explore the potential of targeting mGluR5 for neuroprotection against blood protein-triggered neuroinflammation.
Main Methods:
- Utilized neuronal cultures to assess FG-mediated neurotoxicity and ERK1/2 phosphorylation.
- Examined the effects of direct mGluR5 and mGluR2 activation on FG-mediated microglial activation.
Main Results:
- FG-induced neurotoxicity and ERK1/2 phosphorylation in neurons were significantly reduced by mGluR5 activation, but not mGluR2.
- FG-mediated microglial activation was down-regulated by direct mGluR5 activation on microglia, but not mGluR2.
Conclusions:
- Activation of microglial mGluR5 can protect neurons from the detrimental effects of blood-borne proteins like fibrinogen.
- Targeting microglial mGluR5 presents a promising therapeutic avenue for mitigating innate inflammatory responses in neurodegenerative conditions.
