mGlu3 receptor regulates microglial cell reactivity in neonatal rats
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Updated: Nov 22, 2025
Primary Microglia Isolation from Mixed Glial Cell Cultures of Neonatal Rat Brain Tissue
Published on: August 15, 2012
Manuela Zinni1, Jérôme Mairesse1,2, Julien Pansiot1
1Inserm UMR1141 NeuroDiderot, Univ. Paris Diderot, Sorbonne Paris Cité, Paris, France.
Insights
Perinatal inflammation increases brain vulnerability in newborns. Metabotropic glutamate receptor 3 (mGlu3 receptor) activation in developing microglia mitigates this inflammation, protecting against brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Perinatal inflammation, linked to preterm birth and IUGR, elevates neonatal brain vulnerability and neurodevelopmental disorders.
- Microglia, the brain's immune cells, are activated by systemic inflammation and critically modulate brain injury risk.
- The role of metabotropic glutamate receptor 3 (mGlu3 receptor) in developing microglia during neuroinflammation remains largely unexplored.
Purpose of the Study:
- To investigate the role of mGlu3 receptors in microglial reactivity within the context of perinatal brain injury.
- To determine the effect of perinatal inflammation on mGlu3 receptor expression in developing microglia.
- To explore the therapeutic potential of modulating mGlu3 receptor activity to prevent perinatal brain injury.
Main Methods:
- A rat model was established using a gestational low-protein diet and IL-1β injections to simulate IUGR and perinatal inflammation.
- mGlu3 receptor expression and its impact on microglial activation were analyzed using transcriptomic, pharmacological, histological, and genetic techniques.
- The study involved pharmacological agonists and antagonists, siRNA, and genetic knockout of mGlu3 receptors.
Main Results:
- Perinatal inflammation (LPD/IL-1β) significantly downregulated Grm3 gene expression in developing microglia.
- mGlu3 receptor activation suppressed microglial inflammatory responses to the LPD/IL-1β challenge.
- Blocking or removing mGlu3 receptors exacerbated microglial pro-inflammatory activity, mirroring the effects of perinatal inflammation.
Conclusions:
- Grm3 plays a crucial role in regulating microglial reactivity in the immature brain.
- Targeting mGlu3 receptors offers a potential strategy to prevent brain damage caused by perinatal inflammation.
Background:
Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intra-uterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. Systemic inflammation is recognized to activate microglia, known to be the critical modulators of brain vulnerability. Although some evidence supports a role for metabotropic glutamate receptor 3 (mGlu3 receptor) in modulation of neuroinflammation, its functions are still unknown in the developing microglia.
Methods:
We used a double-hit rat model of perinatal brain injury induced by a gestational low-protein diet combined with interleukin-1β injections (LPD/IL-1β), mimicking both IUGR and prematurity-related inflammation. The effect of LPD/IL-1β on mGlu3 receptor expression and the effect of mGlu3 receptor modulation on microglial reactivity were investigated using a combination of pharmacological, histological, and molecular and genetic approaches.
Results:
Exposure to LPD/IL-1β significantly downregulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central role in the control of inflammation in resting and activated microglia. Microglia reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade, siRNA knock-down, and genetic knock-out of mGlu3 receptors mimicked the pro-inflammatory phenotype observed in microglial cells exposed to LPD/IL-1β.
Conclusions:
Overall, these data show that Grm3 plays a central role in the regulation of microglial reactivity in the immature brain. Selective pharmacological activation of mGlu3 receptors may prevent inflammatory-induced perinatal brain injury.
