ArticleMolecular psychiatry2017
mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions.
Article in Molecular psychiatry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 57 citations in OpenAlex.
- Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020Trial
- GlyT1 inhibition enhances working memory in the mouse TUNL task and normalizes NMDA antagonist-induced network activity.Psychopharmacology · 2026Article
- No evidence for direct physical interaction of 5-HTbioRxiv : the preprint server for biology · 2026Article
- Inflammatory mechanisms underlying early Alzheimer's disease pathology: evidence from the aging rhesus macaque brain.Frontiers in cellular neuroscience · 2026Review
- Region-specific proteomic analysis of aging rhesus macaques following chronic glutamate-carboxypeptidase-II (GCPII) inhibition elucidates potential treatment strategies for sporadic Alzheimer's disease.bioRxiv : the preprint server for biology · 2025Article
- mGlu2 Receptors in the Basal Ganglia: A New Frontier in Addiction Therapy.Frontiers in bioscience (Landmark edition) · 2025Review
- Regional and aging-specific cellular architecture of non-human primate brains.Genome medicine · 2025Article
- Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function.Advances in pharmacology (San Diego, Calif.) · 2025Review
- A Case Series of Anti-Metabotropic Glutamate Receptor 2 Antibody-Related Diseases with Distinct Neurological Involvement.ImmunoTargets and therapy · 2025Article
- Metabotropic glutamate receptors-guardians and gatekeepers in neonatal hypoxic-ischemic brain injury.Pharmacological reports : PR · 2024Review
- Impairments in the early consolidation of spatial memories via group II mGluR agonism in the mammillary bodies.Scientific reports · 2024Article
- Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects.Translational psychiatry · 2024Article
- Gene Expression at the Tripartite Synapse: Bridging the Gap Between Neurons and Astrocytes.Advances in neurobiology · 2024Review
- Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease.Cerebral cortex (New York, N.Y. : 1991) · 2023Article
- Using Nonhuman Primate Models to Reverse-Engineer Prefrontal Circuit Failure Underlying Cognitive Deficits in Schizophrenia.Current topics in behavioral neurosciences · 2023Review
- Exploiting the molecular diversity of the synapse to investigate neuronal communication: A guide through the current toolkit.The European journal of neuroscience · 2022Review
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Glutamate Metabotropic Receptor Type 3 (mGlu3) Localization in the Rat Prelimbic Medial Prefrontal Cortex.Frontiers in neuroanatomy · 2022Article
- Expression of group II and III mGluRs in the carotid body and its role in the carotid chemoreceptor response to acute hypoxia.Frontiers in physiology · 2022Article
- Using rat operant delayed match-to-sample task to identify neural substrates recruited with increased working memory load.Learning & memory (Cold Spring Harbor, N.Y.) · 2020Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
Cognitive deficits in psychiatric and age-related disorders generally involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), but there are few treatments for these debilitating symptoms. Group II metabotropic glutamate receptors (mGluR2/3), which couple to Gi/Go, have been a focus of therapeutics based on rodent research, where mGluR2/3 have been shown to reduce axonal glutamate release and increase glial glutamate uptake. However, this strategy has had mixed results in patients, and understanding mGluR2/3 mechanisms in primates will help guide therapeutic interventions. The current study examined mGluR2/3 localization and actions in the primate dlPFC layer III circuits underlying working memory, where the persistent firing of 'Delay cells' is mediated by N-methyl-d-aspartate receptors and weakened by cAMP-PKA-potassium channel signaling in dendritic spines. Immunoelectron microscopy identified postsynaptic mGluR2/3 in the spines, in addition to the traditional presynaptic and astrocytic locations. In vivo iontophoretic application of the mGluR2/3 agonists (2R, 4R)-APDC or LY379268 onto dlPFC Delay cells produced an inverted-U effect on working memory representation, with enhanced neuronal firing following low doses of mGluR2/3 agonists. The enhancing effects were reversed by an mGluR2/3 antagonist or by activating cAMP signaling, consistent with mGluR2/3 inhibiting postsynaptic cAMP signaling in spines. Systemic administration of these agonists to monkeys performing a working memory task also produced an inverted-U dose-response, where low doses improved performance but higher doses, similar to clinical trials, had mixed effects. Our data suggest that low doses of mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function.
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