mGlu3 receptor regulates microglial cell reactivity in neonatal rats

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 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.

Dendrimer-2PMPA selectively blocks upregulated microglial GCPII activity and improves cognition in a mouse model of multiple sclerosis

“…In support of this hypothesis, it was recently reported that mGluR3 enhances synaptic strength in primate dorsolateral prefrontal cortex via cAMP-PKA-K+ signaling regulation, and that NAAG-mediated mGluR3 stimulation enhances delayed cell firing during working memory tasks [64,65]. In line with our findings, a recent study reported a downregulation in microglia mGluR3 gene expression in a rat model of perinatal brain injury [66]. Similarly, mGluR3 gene expression was upregulated in individuals with MS who responded positively to interferon beta therapy [67].…”