The proposed research will provide the first study of metabotropic glutamate receptor mGluR2/3 influences on dorsolateral prefrontal cortex (dlPFC) function in primates, a brain region greatly afflicted in patients with schizophrenia. Group II metabotropic glutamate receptors (mGluR2, mGluR3) are potential therapeutic targets, and genetic alterations of mGluR3 are increasingly associated with schizophrenia. However, there has been no research on how these receptors influence dlPFC circuits in primates, where there are likely evolutionary differences. The proposed research will determine the pre- vs. post-synaptic location of mGluR2 vs. mGluR3 in primate dlPFC circuits, and how mGluR2/3 stimulation influences dlPFC neuronal firing and cognitive function. As selective mGluR2 and mGluR3 agents are now available for research use, the proposed research will begin to dissect mGluR2 vs. mGluR3 effects on neuronal firing and cognitive performance. Preliminary data show that low doses of an mGluR2/3 agonist can enhance dlPFC neuronal firing and improve working memory performance in monkeys, with no evident side effects, suggesting clinical potential.
Aim 1 will use multiple label, immunoelectron microscopy to localize mGluR2 and mGluR3 in pre- vs. post-synaptic sites in the primate dlPFC. Although rodent studies have focused on pre-synaptic localization, preliminary data from primate dlPFC indicate that mGluR2/3 are also localized post-synaptically next to layer III excitatory synapses, positioned to strengthen network firing. Localization in dlPFC will be compared to that in orbital PFC, temporal cortex and primary visual cortex, to see if the pattern in dlPFC is unique, or extends to other association and/or sensory cortices.
Aim 2 will perform single unit recording of dlPFC neurons in monkeys performing a spatial working memory task to observe how alterations in mGluR2/3 signaling influence task-related network firing. These studies will be able to observe whether a drug treatment decreases neuronal firing (consistent with pre- synaptic inhibition of glutamate release), or increases neuronal firing (consistent with post-synaptic inhibition of cAMP-K+ channel actions). Results with mixed mGluR2/3 compounds will be compared to newly available, selective mGluR2 and mGluR3 agents to begin to define specific influences on dlPFC neuronal firing. Preliminary data indicate that low doses of an mGluR2/3 agonist greatly enhance the firing of dlPFC Delay cells that maintain working memory.
Aim 3 will characterize the behavioral effects of the compounds used in Aim 2, in monkeys performing a battery of cognitive tasks. Initial data indicate that low doses of the mGlu2/3 agonist, (2R,4R)-APDC, markedly improve working memory performance with few side effects, highlighting the therapeutic potential of these mechanisms. The proposed experiments will compare the effects of mGluR2/3 compounds to those of selective mGluR2 and mGluR3 agents to see which receptor(s) underlie the cognitive enhancement. These data will provide essential information for guiding therapeutic strategies for cognitive enhancement in schizophrenia, and for understanding how insults to mGluR3 can impact cognitive function.

Public Health Relevance

Schizophrenia is a devastating disorder, and current treatments do not restore the high order cognitive functions needed to support independent living. The proposed research will determine how the family of Group II metabotropic glutamate receptors influences the higher cognitive functioning of the dorsolateral prefrontal cortex, a higher brain region that is markedly afflicted in schizophrenia. We hope to identify mechanisms that strengthen prefrontal cortical function that can optimize the development of effective treatments for cognitive deficits in schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Osborn, Bettina D
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Yale University
Schools of Medicine
New Haven
United States
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