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Cited by 489Neuroscience and Neuropharmacology ResearchNeural dynamics and brain functionNeurotransmitter Receptor Influence on Behavior

NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex

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Wang, Min, Yang, Yang, Wang, Ching-Jung, Gamo, Nao J., Jin, Lu E., Mazer, James A., Morrison, John H., Wang, Xiao-Jing +1 more·2013·Neuron
DOI 10.1016/j.neuron.2012.12.032PMC PMC3584418
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Abstract

Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPARs) contributed background depolarization to sustain network firing. In contrast, many Response cells were sensitive to AMPAR blockade and increased firing after systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer's disease profoundly impair cognition.

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Crossref · 10.1016/j.neuron.2012.12.032

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  • Delay cells in dlPFC rely heavily on NMDAR, including NR2B subunits, and little on AMPAR.

    “In contrast, the work of Min Wang and colleagues (Wang et al., 2013) have shown that Delay cells in the dlPFC have remarkably little reliance on AMPAR, and instead rely heavily on NMDAR, including NMDAR with NR2B subunits, that close slowly and transfer large amounts of calcium (Ca2+) into the spine (Fig. 2D).”

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

    The Results (page unavailable) show that NR2B NMDAR blockade markedly suppressed Delay-cell firing, while AMPAR blockade had a more modest, delayed effect. The Discussion (page unavailable) describes slower NR2B kinetics and calcium entry through NR2B, but does not establish the citing sentence’s claim that these receptors transfer large amounts of calcium into the spine. (LLM, conf=0.84)

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  • 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 [10]

    The Results and Discussion report that AMPARs provide background depolarization that permits NMDAR activity, and that AMPAR blockade generally affected Delay-cell firing less than NMDAR blockade. They do not establish that AMPARs make only a minor contribution to the permissive depolarization itself; AMPAR blockade significantly reduced firing in many Delay cells. The nicotinic α7 statement has a separate citation in the citing sentence. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • These neurons are modulated in a more classical manner-for example, with a reliance on AMPAR actions-consistent with the higher expression of AMPAR in layer V of monkey dlPFC.

    “These neurons are modulated in a more classical manner—for example, with a reliance on AMPAR actions10—consistent with the higher expression of AMPAR in layer V of monkey dlPFC12.”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [10]

    The Results (Physiological recordings; page unavailable) show that AMPAR blockade reduced firing in post-saccadic Response cells, supporting AMPAR involvement. It had no effect on the tested peri-saccadic Response cells, so the source does not support a general reliance on AMPAR across Response cells. The separate claim about higher layer V AMPAR expression is attached to citation 12, not this source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Pyramidal cells interconnect on dendritic spines through glutamatergic NMDA receptor type NR2B synapses.

    “Pyramidal cells interconnect on dendritic spines through glutamatergic NMDA receptor (NMDAR) type NR2B synapses10 (Fig. 3).”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [10]

  • Cortical network models predict that NMDA receptors subserve the recurrent synaptic excitation and persistent firing of PFC pyramidal neurons during working memory.

    “Cortical network models predict that NMDA receptors subserve the recurrent synaptic excitation and persist firing of PFC pyramidal neurons during working memory 7,8.”

    From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [8]

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Authors
Wang, M., Yang, Y., Wang, C.-J., Gamo, N. J., Jin, L. E., Mazer, J. A., Morrison, J. H., Wang, X.-J., & Arnsten, A. F. T.
Affiliations
  • Yale University (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Arnsten, Amy F.T.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2013-02
Volume
77
Issue
4
Pages
736-749
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2012.12.032
PMC
PMC3584418
OpenAlex
W1986542309
Cited by
489
References
88
Citations by year
2026: 31 · 2025: 37 · 2024: 39 · 2023: 33 · 2022: 26 · 2021: 47 · 2020: 44 · 2019: 20 · 2018: 34 · 2017: 36 · 2016: 37 · 2015: 46 · 2014: 37 · 2013: 20
FWCI
22.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (RL1AA017536)
  • National Institute on Aging (AG 016765, AG-06647, P01AG016765, P01AG030004, R37AG006647)
  • National Institute of Mental Health (MH 062349, R01MH062349, MH 09335401, R01MH093354)
  • National Center for Research Resources (U54RR024350)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
NMDA receptor, NR2B subunit, working memory, dorsolateral prefrontal cortex, delay cell, AMPA receptors, ketamine, recurrent excitation, glutamate receptor blockade, computational modeling, schizophrenia, Alzheimer's disease, primate prefrontal cortex
MeSH terms
Animals, Brain Mapping, Computer Simulation, Macaca mulatta, Male, Memory, Short-Term, Models, Neurological, Neurons, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Pyramidal Cells, Receptors, AMPA

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