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Cited by 188Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchNeural dynamics and brain function

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

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Yang, Yang, Paspalas, Constantinos D., Jin, Lu E., Picciotto, Marina R., Arnsten, Amy F. T., Wang, Min·2013·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1307849110PMC PMC3718126
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Abstract

The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510-1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477-485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade of α7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110-1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia.

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  • Cholinergic stimulation of nic-α7R in layer III dlPFC is permissive for NMDAR stimulation.

    “Her work with Yang Yang showed that cholinergic stimulation of nic-α7R, which are localized within the glutamate PSD in layer III dlPFC, are permissive for NMDAR stimulation (Fig. 2D; (Yang et al., 2013)).”

    From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Yang et al., 2013

  • The permissive depolarization of the postsynaptic density needed for NMDAR opening is provided by cholinergic stimulation of nicotinic α7 receptors in the postsynaptic density with only minor contributions from AMPA-type glutamate receptors.

    “The permissive depolarization of the postsynaptic density needed for NMDAR opening is provided by cholinergic stimulation of nicotinic α7 receptors in the postsynaptic density11 with only minor contributions from AMPA-type glutamate receptors (AMPAR)10, consistent with the lower expression of AMPAR in layer III (ref. 12).”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [11]

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Cited by

Sorted by citations

Authors
Yang, Y., Paspalas, C. D., Jin, L. E., Picciotto, M. R., Arnsten, A. F. T., & Wang, M.
Affiliations
Yale University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2013-07
Volume
110
Issue
29
Pages
12078-12083
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1307849110
PMC
PMC3718126
OpenAlex
W2050302780
Cited by
188
References
7
Citations by year
2026: 9 · 2025: 7 · 2024: 18 · 2023: 13 · 2022: 11 · 2021: 19 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 21 · 2016: 12 · 2015: 23 · 2014: 21
FWCI
8.37
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • American Federation for Aging Research
  • National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
  • National Institute on Aging (P01AG030004)
  • National Institute of Mental Health (R01MH093354, R01MH077681)
  • National Institute on Drug Abuse (DA14241, R01DA014241, R37DA014241)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
NMDA receptor, dorsolateral prefrontal cortex, working memory, glutamatergic synapses, acetylcholine, visual representation of space, schizophrenia, arousal, sleep-wake states, primate prefrontal cortex
MeSH terms
Acetylcholine, Aconitine, Analysis of Variance, Animals, Cognition, Female, Iontophoresis, Macaca mulatta, Male, Mecamylamine, Phenols, Piperidines, Quinuclidines, Receptors, Nicotinic, Spatial Behavior, Synapses, Visual Perception, N-Methylaspartate, Microscopy, Immunoelectron, Prefrontal Cortex, Cholinergic Agonists, Cholinergic Antagonists, Bridged Bicyclo Compounds, Heterocyclic, alpha7 Nicotinic Acetylcholine Receptor

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