2. Academic Validation
  3. mGlu3 receptor regulates microglial cell reactivity in neonatal rats

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

  • J Neuroinflammation. 2021 Jan 6;18(1):13. doi: 10.1186/s12974-020-02049-z.
Manuela Zinni 1,  Jérôme Mairesse 1 2,  Julien Pansiot 1,  Francesco Fazio 3,  Luisa Iacovelli 4,  Nico Antenucci 4,  Rosamaria Orlando 4,  Ferdinando Nicoletti 3 4,  Daniel Vaiman 5,  Olivier Baud 6 7 8
Affiliations

Affiliations

  • 1 Inserm UMR1141 NeuroDiderot, Univ. Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • 2 Laboratory of Child Growth and Development, University of Geneva, Geneva, Switzerland.
  • 3 IRCCS Neuromed, Pozzilli, Italy.
  • 4 Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
  • 5 Institut Cochin, Inserm U1016, UMR8104 CNRS, Paris, France.
  • 6 Inserm UMR1141 NeuroDiderot, Univ. Paris Diderot, Sorbonne Paris Cité, Paris, France. [email protected].
  • 7 Laboratory of Child Growth and Development, University of Geneva, Geneva, Switzerland. [email protected].
  • 8 Division of Neonatology and Pediatric Intensive Care, Children's University Hospital of Geneva, Geneva, Switzerland. [email protected].
PMID: 33407565 DOI: 10.1186/s12974-020-02049-z
Abstract

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.

Keywords

Microglia reactivity; Perinatal neuroinflammation; mGlu3 receptor.

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