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 support 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 approaches.Results: Exposure to LPD/IL-1β significantly down-regulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central position in the control of inflammation in resting and activated microglia. Microglia hyper-reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade and siRNA knock-down of mGlu3 receptors in control microglia 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.

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Brain injuries and subsequent neurodevelopmental impairments observed following Fetal Growth Restriction (FGR) were shown to be associated with an exacerbated neonatal neuro-inflammation. The aim of this work was to characterize a rat model of FGR by advanced diffusion MRI (DTI and NODDI) and functional ultrasounds (fUS). We show in this study that neonatal inflammation lead to transient microstructural damages and subsequent behavioral and functional disabilities at long term. This model mimics very closely clinical reality in babies born following FGR. Innovative neuroimaging tools associated with this neuro-inflammatory model pave the way for their translational use in human neonates.