title: mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions.
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.
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: L E
authors: LE
authors: Jin
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: M
authors: M
authors: Wang
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: S-T
authors: ST
authors: Yang
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: Y
authors: Y
authors: Yang
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: V C
authors: VC
authors: Galvin
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: T C
authors: TC
authors: Lightbourne
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: D
authors: D
authors: Ottenheimer
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: Q
authors: Q
authors: Zhong
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: J
authors: J
authors: Stein
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: A
authors: A
authors: Raja
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: C D
authors: CD
authors: Paspalas
authors: Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, USA.
authors: A F T
authors: AFT
authors: Arnsten
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D055366:Synaptic Potentials / Q000502:physiology
chemical_list: D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid