title: mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks.
abstract: The newly evolved circuits in layer III of primate dorsolateral prefrontal cortex (dlPFC) generate the neural representations that subserve working memory. These circuits are weakened by increased cAMP-K+ channel signaling, and are a focus of pathology in schizophrenia, aging, and Alzheimer's disease. Cognitive deficits in these disorders are increasingly associated with insults to mGluR3 metabotropic glutamate receptors, while reductions in mGluR2 appear protective. This has been perplexing, as mGluR3 has been considered glial receptors, and mGluR2 and mGluR3 have been thought to have similar functions, reducing glutamate transmission. We have discovered that, in addition to their astrocytic expression, mGluR3 is concentrated postsynaptically in spine synapses of layer III dlPFC, positioned to strengthen connectivity by inhibiting postsynaptic cAMP-K+ channel actions. In contrast, mGluR2 is principally presynaptic as expected, with only a minor postsynaptic component. Functionally, increase in the endogenous mGluR3 agonist, N-acetylaspartylglutamate, markedly enhanced dlPFC Delay cell firing during a working memory task via inhibition of cAMP signaling, while the mGluR2 positive allosteric modulator, BINA, produced an inverted-U dose-response on dlPFC Delay cell firing and working memory performance. These data illuminate why insults to mGluR3 would erode cognitive abilities, and support mGluR3 as a novel therapeutic target for higher cognitive disorders.
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Lu E
authors.initials: LE
authors.lastname: Jin
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Veronica C
authors.initials: VC
authors.lastname: Galvin
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Taber C
authors.initials: TC
authors.lastname: Lightbourne
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt UniversityMedical Center, Nashville, TN 37232-0697, USA.
authors.forename: Peter Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Amy F T
authors.initials: AFT
authors.lastname: Arnsten
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Constantinos D
authors.initials: CD
authors.lastname: Paspalas
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005133:Eye Movements / Q000187:drug effects / Q000502:physiology; D005260:Female; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D057907:Post-Synaptic Density / Q000378:metabolism* / Q000648:ultrastructure; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism* / Q000648:ultrastructure; D065853:Spatial Learning / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects
chemical_list: D018683:Excitatory Amino Acid Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3
keywords: Alzheimer's disease; GRM2; GRM3; dendritic spine; schizophrenia