Presynaptic and postsynaptic mGluR2/3 modulate glutamatergic network synapses in layer III of the primate dorsolateral prefrontal cortex (dlPFC). (a) A schematic illustration of mGluR2/3 locations and likely actions in the axospinous glutamatergic synapse. mGluR2/3 are in their traditional location on glutamatergic axons to reduce glutamate release, and on astrocytes, where they promote glutamate uptake from the synapse. Both actions would reduce neuronal firing of layer III recurrent excitatory networks. However, the current study also uncovered postsynaptic mGluR2/3 on dendritic spines, positioned to inhibit cAMP opening of K+ channels and thus enhance neuronal firing, consistent with physiological data from this study. As these layer III circuits are underactive in schizophrenia and aging, potential therapeutic effects of mGluR2/3 agonists may arise from stimulation of these postsynaptic receptors. (b) Immunogold labeling against the shared intracellular sequence of mGluR2 and mGluR3 demonstrates mGluR2/3 expression in their traditional presynaptic location (red arrowheads), bordering the synapse of a glutamatergic-like axon terminal (pink-pseudocolored), but also postsynaptically (yellow arrowhead), next to the synapse on the dendritic spine (yellow-pseudocolored). (c) Glial mGluR2/3 (blue arrowheads) are in their traditional location in astrocytic processes (cyan-pseudocolored), including expression near the synapse, where they can modulate glutamate uptake. Synapses in b and c are between arrows. HCN/KCNQ, hyperpolarization-activated cyclic nucleotide-gated and Kv7. Scale bars: 100 nm. For more information on this topic, please refer to the article by Jin et al. on pages 1615–1625.
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