Muscarinic M1 Receptors Modulate Working Memory Performance and Activity via KCNQ Potassium Channels in the Primate Prefrontal Cortex
Open accessAbstract
Working memory relies on the dorsolateral prefrontal cortex (dlPFC), where microcircuits of pyramidal neurons enable persistent firing in the absence of sensory input, maintaining information through recurrent excitation. This activity relies on acetylcholine, although the molecular mechanisms for this dependence are not thoroughly understood. This study investigated the role of muscarinic M1 receptors (M1Rs) in the dlPFC using iontophoresis coupled with single-unit recordings from aging monkeys with naturally occurring cholinergic depletion. We found that M1R stimulation produced an inverted-U dose response on cell firing and behavioral performance when given systemically to aged monkeys. Immunoelectron microscopy localized KCNQ isoforms (Kv7.2, Kv7.3, and Kv7.5) on layer III dendrites and spines, similar to M1Rs. Iontophoretic manipulation of KCNQ channels altered cell firing and reversed the effects of M1R compounds, suggesting that KCNQ channels are one mechanism for M1R actions in the dlPFC. These results indicate that M1Rs may be an appropriate target to treat cognitive disorders with cholinergic alterations.
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In rat and primate PFC, the α2-adrenoceptor and muscarinic M1 receptor modulate working memory via KCNQ potassium channels.
“Recent studies of rat and primate PFC showed that the α2-adrenoceptor and muscarinic M1 receptor modulate working memory via KCNQ potassium channel [148–151].”
From Development of prefrontal cortex (2022) · cites this paper as [151]
In the PFC of nonhuman primates, the muscarinic M1 receptors modulate working memory via KCNQ potassium channels.
“In the PFC of nonhuman primates, the muscarinic M1 receptors modulate working memory via KCNQ potassium channels [151].”
From Development of prefrontal cortex (2022) · cites this paper as [151]
In aged monkeys with naturally occurring cholinergic depletion, low-dose muscarinic M1R stimulation enhances delay firing in dorsolateral PFC neurons and improves working memory via mechanism involving KCNQ channels.
“In aged monkeys with naturally occurring cholinergic depletion, low-dose muscarinic M1R stimulation enhances delay firing in dorsolateral PFC neurons and improves working memory via a mechanism involving KCNQ channels 248.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [248]
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References 76 · Cited by 79
- Authors
- Galvin, V. C., Yang, S. T., Paspalas, C. D., Yang, Y., Jin, L. E., Datta, D., Morozov, Y. M., Lightbourne, T. C., Lowet, A. S., Rakic, P., Arnsten, A. F. T., & Wang, M.
- Affiliations
- Yale University (US)
- Corresponding author
- Wang, Min
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 106
- Issue
- 4
- Pages
- 649-661.e4
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7244366
- OpenAlex
- W3012489854
- Cited by
- 79
- References
- 76
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 14 · 2023: 13 · 2022: 15 · 2021: 16 · 2020: 4
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Brain and Behavior Research Foundation (U54RR024350, 1RL1AA017536)
- National Institutes of Health (1RL1AA017536, R01 MH093354)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- M1 muscarinic receptor, working memory, dorsolateral prefrontal cortex, KCNQ potassium channels, Kv7.2, Kv7.3, Kv7.5, cholinergic depletion, acetylcholine, aged monkeys, iontophoresis, cognitive disorders
- MeSH terms
- Animals, Female, Macaca mulatta, Male, Memory, Short-Term, Neurons, Prefrontal Cortex, Receptor, Muscarinic M1, KCNQ Potassium Channels
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