MGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: Evidence for both presynaptic and postsynaptic actions

L. E. Jin, M. Wang, S. T. Yang, Y. Yang, V. C. Galvin, T. C. Lightbourne, D. Ottenheimer, Q. Zhong, J. Stein, A. Raja, C. D. Paspalas, A. F.T. Arnsten

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19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1615-1625
Number of pages11
JournalMolecular Psychiatry
Volume22
Issue number11
DOIs
StatePublished - Nov 1 2017

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Jin, L. E., Wang, M., Yang, S. T., Yang, Y., Galvin, V. C., Lightbourne, T. C., Ottenheimer, D., Zhong, Q., Stein, J., Raja, A., Paspalas, C. D., & Arnsten, A. F. T. (2017). MGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: Evidence for both presynaptic and postsynaptic actions. Molecular Psychiatry, 22(11), 1615-1625. https://doi.org/10.1038/mp.2016.129