Glutamate is considered the primary excitatory neurotransmitter of the central nervous system and has an important role in all aspects of brain function including the modulation of synaptic plasticity [40,41]. The release and concentration of glutamate are tightly regulated to ensure proper function at its targets, the glutamate receptors. These are divided into ionotropic glutamate receptors (iGlu) and metabotropic glutamate receptors (mGlu). While iGlu such as N-methyl-D-aspartate receptor (NMDAR), kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid receptors (AMPAR) are ligand-gated ion channels that generate excitatory currents, mGlu are G-protein-coupled receptors (GPCRs) that activate second messenger signaling pathways and modulate synaptic transmission and plasticity on a longer scale [42]. The coordinated functions of iGlu and mGlu regulate the neural glutamate signaling, and dysfunctions or imbalances of these receptors, especially mGlu, have been implicated in various neuropsychiatric diseases [43,44].

mGlu exist as constitutive dimers and can be further subdivided into class I, II and III [45]. Class II consists of mGlu2 and mGlu3, which are distributed in various areas of the brain and are mostly detected at the synapse of neurons [43]. There, they are primarily localized in presynaptic locations (excluding the active zone [46]), where they inhibit the release of the neurotransmitter glutamate and gamma-aminobutyric acid (GABA) in excitatory glutamatergic neurons and inhibitory GABAergic interneurons, respectively [45]. Apart from its presynaptic localization, mGlu2/3 is also found throughout the axon, at the postsynaptic membrane and on glia cells [46,47,48,49,50]. The precise localization of mGlu at the synapse determines its synaptic functioning and is dependent on differential mechanisms of trafficking and positioning [51]. Furthermore, species differences have been observed for the localization of mGlu2 and mGlu3: in the primate PFC, mGlu2 is the predominant presynaptic receptor and mGlu3 the predominant postsynaptic receptor, while in the rat PFC both receptors are predominantly found on presynaptic terminals [50,52].

GPCRs mediate signaling through one of the four subfamilies of heteromeric G proteins (G_s, G_i/o, G_q/11 and G_12/13), which consist of an α, β and γ subunit. mGlu2/3 canonically binds to G_i/o and activates related signaling pathways, depending on the molecular localization.

The activation of presynaptic and postsynaptic mGlu2/3 generally results in opposite effects (Figure 1). Downstream signaling pathways of presynaptic mGlu2/3 include the inhibition of adenylyl cyclase and the protein kinase A via G_i/o α subunit, as well as the inhibition of voltage-gated calcium channels (VGCCs) and the activation of G protein-coupled inward rectifying Potassium channels (GIRKs) via G_i/o βγ subunits [53,54,55]. Together, these signaling pathways inhibit the glutamate release in presynaptic glutamatergic neurons and thus provide a feedback mechanism to prevent excessive excitation and induce long-term depression (LTD). Activation of postsynaptic mGlu2/3 on the other site results in G_i/o-mediated NMDAR activation through various protein kinases including PKA, PKB, PKC and glycogen synthase kinase-3 beta (GSK-3B), as well as NMDAR trafficking by Snare proteins [56,57,58,59,60]. The activation of postsynaptic mGlu2/3 can further result in the increased surface expression of AMPAR via GSK-3B and extracellular signal-regulated kinases (ERKs) [61]. Taken together, postsynaptic mGlu2/3s potentiate the NMDAR current and regulate the NMDA/AMPA receptor trafficking, and thus cooperatively induce and maintain long-term potentiation (LTP). These findings demonstrate the sophisticated and opposing molecular mechanism of mGlu2/3 at presynaptic (LTD) and postsynaptic (LTP) locations required to ensure the correct and sustainable glutamatergic neurotransmission in the brain.