Interestingly mGlu and mGlu receptors

Interestingly, mGlu2 and mGlu3 receptors differ notably by their cellular distribution. Whereas mGlu2 receptors are mostly neuronal, mGlu3 receptors are expressed both in glia and in neurons. In neurons, mGlu3 receptors are present at the post-synapse and in presynaptic elements (Tamaru et al., 2001) where their activation reduces synaptic activity and plasticity (Harrison et al., 2008). Interestingly, a functional partnership between neuronal mGlu3 receptors and mGlu5 receptors has recently been described, in which activation of mGlu3 receptors amplifies mGlu5 receptor signaling and shapes the ability of mGlu5 receptors to either amplify or restrain neuronal toxicity (Di Menna et al., 2018). In astrocytes, mGlu3 receptors have been shown to regulate important functions such as the release of astrocytic glutamate and other factors (Aronica et al., 2005; Corti et al., 2007; Nicoletti et al., 2015), the re-uptake of glutamate (Aronica et al., 2003), nitrate Iberiotoxin sale (Wang et al., 2016) and are involved in neuroprotection (Battaglia et al., 2015; Corti et al., 2007). By promoting glutamate sensing in the extracellular space, through the molecular mechanisms described in this study, the mGlu3 receptor could react effectively to concentrations of glutamate below the micromolar range. This might confer mGlu3 receptor the ability to regulate the basal tone of glutamate release from neuronal presynaptic elements, as well as basal release of neuroprotective factors, thereby participating to the fine regulation of glutamate reuptake by glia. Given the numerous physiological and pathological actions of glutamate, it is crucial to control acutely extracellular glutamate concentrations in the brain. Indeed glutamate becomes neurotoxic at elevated extracellular concentrations and glutamate dysregulation is associated to many CNS disorders. Different actors ensure the control of glutamate homeostasis. Transporters are maintaining low concentrations of synaptic and extrasynaptic glutamate. While ionotropic glutamate receptors are responsible of the fast-synaptic response to glutamate, mGluRs are responsible for its slow neuromodulatory actions. Group I mGluRs positively modulate responses to glutamate while group II and group III receptors are decreasing neuronal activity by downregulating the release of neurotransmitters. Interestingly, the eight members of the mGluR family display different affinities for glutamate. Three members present submicromolar affinity for glutamate: mGlu1 with 0.3 μM (Mutel et al., 2000; Thomsen et al., 1993), mGlu5 with 0.5 μM (Mutel et al., 2000) and mGlu3 which Ki values range from 0.041 to 0.9 μM (Johnson et al., 1999; Laurie et al., 1995; Schweitzer et al., 2000) and 0.9 μM in the present study. While the mGlu3 receptor affinity for glutamate is in the same range than the ones of mGlu1 or mGlu5 receptors, its relatively high glutamate affinity combined to its unique Cl− lock favoring the agonist-induced state makes the mGlu3 receptor able to sense and fully respond to submicromolar glutamate concentrations. This could enable mGlu3 receptors to play a role in the regulation of basal conditions with low tone of glutamate. Other members of the family, mGlu2, 4,6and 8 receptors present intermediate affinities, in the micromolar range, for glutamate, (Cartmell et al., 1998; Eriksen and Thomsen, 1995; Schweitzer et al., 2000; Wright et al., 2000). On the opposite side of the spectrum, the mGlu7 receptor is activated by millimolar concentrations of glutamate, with an affinity around 900 μM (Wright et al., 2000). This receptor is located in the synaptic grid where glutamate is released and can reach occasionally such high concentrations. Contrary to mGlu3 receptor, the role of mGlu7 receptor would then be to react to the highest concentrations of glutamate and may ensure a role of safety valve. This mGluRs large spectrum of glutamate sensitivity associated to their widespread synaptic, non-synaptic and glial distribution allows them to participate to a fine neuroadaptation of the CNS.