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Effects of blocking mGluR5 on primate dorsolateral prefrontal cortical neuronal firing and working memory performance
Sheng-Tao Yang1, Min Wang1, Veronica Galvin1
1Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA.
Rationale:
Metabotropic glutamate type 5 receptor (mGluR5) antagonists are under development for treating cognitive disorders such as Fragile X syndrome and Alzheimer's disease, largely based on success in mouse models, where post-synaptic mGluR5 stimulation weakens synaptic functions in hippocampus. However, human trials of mGluR5 antagonists have yet to be successful. This may be due in part to the differing effects of mGluR5 in hippocampus vs. prefrontal cortex, as mGluR5 are primarily post-synaptic in rodent hippocampus, but are both pre- and post-synaptic in the dorsolateral prefrontal cortical (dlPFC) circuits known to subserve working memory.
Objectives And Methods:
The current study examined the effects of the selective mGluR5 negative allosteric modulator, MTEP (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride), on neuronal firing and working memory performance in aging rhesus monkeys with naturally occurring impairments in neuronal firing and cognitive performance.
Results:
We found that iontophoresis of MTEP directly onto dlPFC "Delay cells" had an inverted U dose-response, where low doses tended to enhance task-related firing, but higher doses suppressed neuronal firing. Similar effects were seen on cognitive performance following systemic MTEP administration (0.0001-0.1 mg/kg), with MTEP producing erratic dose-response curves. In the subset of monkeys (50%) that showed replicable improvement with MTEP, co-administration with the mGluR5 PAM, CDPPB (3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), blocked MTEP beneficial effects, consistent with mGluR5 actions.
Conclusions:
The mixed effects of MTEP on cognitive performance may arise from opposing actions at pre- vs. post-synaptic mGluR5 in dlPFC. These data from monkeys suggest that future clinical trials should include low doses, and identification of potential subgroup responders.
Insights
Metabotropic glutamate type 5 receptor (mGluR5) antagonists show complex effects on working memory. Low doses of MTEP enhanced neuronal firing and performance in monkeys, while higher doses were detrimental, suggesting potential for targeted therapeutic use.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Metabotropic glutamate type 5 receptor (mGluR5) antagonists are investigated for cognitive disorders like Fragile X and Alzheimer's.
- Previous success in mouse models contrasts with human trial failures, possibly due to regional differences in mGluR5 function (hippocampus vs. prefrontal cortex).
- mGluR5 receptors play distinct roles in rodent hippocampus (post-synaptic) versus primate dorsolateral prefrontal cortex (dlPFC) (pre- and post-synaptic), impacting working memory circuits.
Purpose of the Study:
- To investigate the effects of a selective mGluR5 negative allosteric modulator, MTEP, on neuronal activity and working memory in aging rhesus monkeys.
- To understand the dose-dependent actions of MTEP on dlPFC 'Delay cells' and overall cognitive performance.
Main Methods:
- Iontophoresis of MTEP onto dlPFC 'Delay cells' in aging rhesus monkeys.
- Systemic administration of MTEP (0.0001-0.1 mg/kg) to assess working memory performance.
- Co-administration of MTEP with an mGluR5 positive allosteric modulator (PAM), CDPPB, in a subset of subjects.
Main Results:
- MTEP exhibited an inverted U dose-response on neuronal firing, with low doses enhancing and high doses suppressing activity.
- Systemic MTEP administration resulted in erratic dose-response curves for cognitive performance.
- CDPPB blocked the beneficial effects of MTEP in the 50% of monkeys that showed improvement, confirming mGluR5 involvement.
Conclusions:
- The variable effects of MTEP on cognitive performance may stem from opposing pre- and post-synaptic actions of mGluR5 in the dlPFC.
- Findings suggest that future clinical trials for mGluR5 antagonists should consider low doses and identify potential responder subgroups.
- This non-human primate model provides valuable insights into the complex role of mGluR5 in working memory and potential therapeutic strategies.
