Fig. 1. GCPII-NAAG-mGluR3 signaling in primate dlPFC.

A Traditional view of mGluR3 signaling in a glutamate synapse, where receptors are predominately on presynaptic terminals and on astrocytes, where they reduce glutamate signaling by inhibiting release and increase uptake, respectively. NAAG is co-released with glutamate, and is selective for mGluR3; GCPII catabolism of NAAG would increase neuronal firing in these traditional circuits. B GCPII-NAAG-mGluR3 signaling in layer III of the primate dlPFC, where mGluR3 are not presynaptic, but rather are post-synaptic on spines, and NAAG stimulation of mGluR3 inhibits cAMP-K⁺ channel signaling to increase synaptic efficacy and enhance neuronal firing. Thus, GCPII catabolism of NAAG decreases neuronal firing in these recently evolved circuits. C Multiple label immunofluorescence showing GCPII labeling (magenta) in its traditional localization in astrocytes which are co-labeled with GFAP (cyan); Hoescht (blue) labels nuclei of all cells. One representative astrocyte is outlined by the yellow dashed box in (C. C₁-C₄) correspond to the boxed area in (C). In (C₁–C₄) GCPII labeling clearly outlines the GFAP positive astrocyte soma, as demarcated by the white arrowheads, (C₅) Orthogonal sectioning of this region (corresponding region of interest from C outlined by the yellow box). Selected Z-stack image shows co-localization of GCPII and GFAP (magenta and cyan) across three different planes for one point, as indicated by the crossed dashed lines. The right-side bar demonstrates labeling in the YZ plane, while the bottom bar represents labeling in the XZ plane. D GCPII is also co-localized in neurons (NeuN, green) with a pyramidal cell-like morphology. White arrowheads highlight GCPII labeling in an apical dendrite. Scale bars: (C,D) 10 μm; (C₁-C₄) 5 μm; (C₅) 2.5 μm; (D₁-D₄) 10 μm.