MGlu3 receptor regulates microglial cell reactivity in neonatal rats

Manuela Zinni,Olivier Baud,Jérôme Mairesse,Rosamaria Orlando,Julien Pansiot,Nico Antenucci,Ferdinando Nicoletti,Luisa Iacovelli,Daniel Vaiman,Francesco Fazio

doi:10.1186/s12974-020-02049-z

Abstract

BackgroundPerinatal 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.MethodsWe 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.ResultsExposure 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.ConclusionsOverall, 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.

Highlights

Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intrauterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders
Low-protein diet (LPD)/IL-1β exposure in rats induces downregulation of Grm3 gene expression in microglia We studied the transcriptomic consequences of the combination of gestational LPD and neonatal IL-1β exposure on the glutamatergic system in microglial cells
Bioinformatics analysis performed on microglial cells sorted from P4 rat pups showed consistent significant alterations of the glutamatergic functions in animals subjected to LPD/IL-1β relative to CTRL animals (Fig. 1a)

Summary

Introduction

Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intrauterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR), and 15 million are born preterm [1, 2] These two complications are the leading causes of ante/perinatal stress and brain injury, responsible for neurocognitive and behavioral disorders in more than 9 million children each year. Both prematurity and IUGR are associated with perinatal systemic inflammation, identified to activate microglia [3], the resident macrophages of the central nervous system (CNS), and to be the best predictor of subsequent neurological impairment [4, 5]. The control of microglial activation during this critical period appears to be key in protecting the developing brain

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