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. 2020 Dec 15;26(8):3684–3700. doi: 10.1038/s41380-020-00973-3

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — a Under healthy conditions, feedforward calcium–cAMP signaling in layer III dlPFC spines is held in check by the phosphodiesterases (PDE4s), which catabolize cAMP, and by the G_i/o-linked receptors mGluR3 (shown) and α2A-AR (not shown), which are both localized on spines and inhibit the synthesis of cAMP. mGluR3 are stimulated by glutamate, but also by NAAG, which is coreleased with glutamate and is selective for mGluR3. mGluR3 are also expressed in their traditional location on astrocytes [73], where they promote glutamate uptake. Astrocytes also synthesize GCPII, an enzyme which catabolizes NAAG and reduces mGluR3 signaling. Under healthy conditions, there are relatively low levels of GCPII, and thus strong NAAG stimulation of mGluR3 on spines, which enhances neuronal firing by inhibiting cAMP–PKA opening of K⁺ channels. b ImmunoEM showing mGluR3 labeling (indicated by green arrowheads) on a layer III dlPFC spine in rhesus monkey, next to the glutamate-like synapse (indicated by black arrows) and near the spine apparatus (pseudocolored in pink). Ax axon terminal, sp spine. c A variety of environmental and genetic insults associated with schizophrenia effect proteins that play key roles in layer III dlPFC spines. These insults include alterations that weaken NMDAR transmission (which are essential to pyramidal cell firing, but have less influence on interneurons in adult primate dlPFC [184]), as well as insults that weaken the regulation of feedforward calcium–cAMP signaling in spines. When these insults occur early in life (genetic or perinatal insults), they may induce atrophy of higher cortical circuits that are apparent in childhood, adolescence, or young adulthood. These insults may involve inflammatory events, which increase GCPII expression [140], and/or genetic alterations such as insults to GRM3 (mGluR3) or to DISC1, which are associated with increased risk of schizophrenia. Dysregulation of feedforward calcium–cAMP signaling would lead to excessive opening of nearby K⁺ channels, weaker synaptic connectivity and spine loss, and reduction in the persistent firing needed for higher cognition. d Iontophoresis of the GCPII inhibitor, ZJ43, onto a dlPFC delay cell enhances the persistent firing during the delay period in a monkey performing a working memory task. Images b and d were adapted with permission from Jin et al. [73].