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 NMDA 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 dose mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function.

Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

“…For example, both noradrenergic α 2A-AR and glutamatergic mGluR3 are concentrated on spines, where they enhance delay cell firing by inhibiting cAMP–K + channel signaling. 134,145 In contrast, mGluR2 are localized presynaptically, where they inhibit glutamate release. 146 Another critical regulator of feedforward cAMP–calcium signaling in newly evolved dlPFC layer III microcircuits is the phosphodiesterase, PDE4A, which catabolizes cAMP and is anchored to the spine apparatus by the scaffolding protein Disrupted in Schizophrenia (DISC1).…”

“…212 Physiological recordings from monkeys show that NAAG stimulation of mGluR3 in dlPFC greatly enhances delay cell firing by inhibiting cAMP–K+ channels signaling. 145 NAAG activity is inhibited by the NAAG peptidase GCPII. 213 A NAAG peptidase inhibitor markedly increased the firing of delay cells, 146 suggesting these agents may have therapeutic potential.…”

“…As postmortem studies have revealed increased protein levels of GCPII and reduced levels of mGluR3 in the dlPFC in subjects with schizophrenia, 186 GCPII inhibitors might be an effective approach to increase endogenous NAAG levels to curb feedforward cAMP–calcium signaling. Low doses of mGluR2/3 agonists that preferentially engage postsynaptic actions also enhance delay cell firing and improve working memory in monkeys, 145 and a meta-analysis of mGluR2/3 agonist effects in patients with schizophrenia has shown that low (but not high) doses of mGluR2/3 agonists can be beneficial in patients in early stages of the illness. 214 Thus, data from patients with the illness encourage this strategy.…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…Group II mGlu receptors are widely expressed in brain regions relevant to drug-related behaviors. Although physiological actions of postsynaptic group II mGlu receptors have been identified (for example see Otani et al, 2002; Walker et al, 2015; Jin et al, 2016), they are best known for their ability to inhibit presynaptic neurotransmitter release at glutamatergic terminals. Group II mGlu receptor activation depresses glutamate release in critical regions such as the mPFC (Otani et al, 1999, 2002; Huang and Hsu, 2008; Walker et al, 2015), dorsal striatum (Lovinger and McCool, 1995; Kahn et al, 2001), NAc (Manzoni et al, 1997; Robbe et al, 2002a,b), central amygdala (Neugebauer et al, 2000), and BNST (Grueter and Winder, 2005).…”

Contribution of heteromerization to G protein-coupled receptor function

“…Accordingly, it was suggested that the mGlu2 receptor was expressed both pre- and post-synaptically in the frontal cortex [80,81], an hypothesis that has been validated recently [82]. Using neuroanatomical approaches such as fluorescent in situ hybridization (FISH) [36] and immunohistochemistry [83], it was demonstrated that 5-HT 2A and mGlu2 co-localized in layer V mouse cortical pyramidal neurons.…”