NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders
The dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the g...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Psychiatry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2021.654322/full |
| _version_ | 1818726600750923776 |
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| author | Shengtao Yang Hyojung Seo Hyojung Seo Min Wang Amy F. T. Arnsten |
| author_facet | Shengtao Yang Hyojung Seo Hyojung Seo Min Wang Amy F. T. Arnsten |
| author_sort | Shengtao Yang |
| collection | DOAJ |
| description | The dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the generation of mental representations during working memory relies on NMDAR neurotransmission, with surprisingly little contribution from AMPAR. Systemic administration of low “antidepressant” doses of the NMDAR antagonist, ketamine, erodes these representations and reduces dlPFC Delay cell firing. In contrast to the dlPFC, V1 neuronal firing to visual stimuli depends on AMPAR, with much less contribution from NMDAR. Similarly, neurons in the dlPFC that respond to sensory events (cue cells, response feedback cells) rely on AMPAR, and systemic ketamine increases their firing. Insults to NMDAR transmission, and the impaired ability for dlPFC to generate mental representations, may contribute to cognitive deficits in schizophrenia, e.g., from genetic insults that weaken NMDAR transmission, or from blockade of NMDAR by kynurenic acid. Elevated levels of kynurenic acid in dlPFC may also contribute to cognitive deficits in other disorders with pronounced neuroinflammation (e.g., Alzheimer's disease), or peripheral infections where kynurenine can enter brain (e.g., delirium from sepsis, “brain fog” in COVID19). Much less is known about NMDAR actions in the primate cingulate cortices. However, NMDAR neurotransmission appears to process the affective and visceral responses to pain and other aversive experiences mediated by the cingulate cortices, which may contribute to sustained alterations in mood state. We hypothesize that the very rapid, antidepressant effects of intranasal ketamine may involve the disruption of NMDAR-generated aversive mood states by the anterior and subgenual cingulate cortices, providing a “foot in the door” to allow the subsequent return of top-down regulation by higher PFC areas. Thus, the detrimental vs. therapeutic effects of NMDAR blockade may be circuit dependent. |
| first_indexed | 2024-12-17T22:00:47Z |
| format | Article |
| id | doaj.art-d99832f79e4443afbadb9525d9405b75 |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-12-17T22:00:47Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-d99832f79e4443afbadb9525d9405b752022-12-21T21:31:00ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402021-04-011210.3389/fpsyt.2021.654322654322NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental DisordersShengtao Yang0Hyojung Seo1Hyojung Seo2Min Wang3Amy F. T. Arnsten4Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Neuroscience, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Neuroscience, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Neuroscience, Yale University School of Medicine, New Haven, CT, United StatesThe dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the generation of mental representations during working memory relies on NMDAR neurotransmission, with surprisingly little contribution from AMPAR. Systemic administration of low “antidepressant” doses of the NMDAR antagonist, ketamine, erodes these representations and reduces dlPFC Delay cell firing. In contrast to the dlPFC, V1 neuronal firing to visual stimuli depends on AMPAR, with much less contribution from NMDAR. Similarly, neurons in the dlPFC that respond to sensory events (cue cells, response feedback cells) rely on AMPAR, and systemic ketamine increases their firing. Insults to NMDAR transmission, and the impaired ability for dlPFC to generate mental representations, may contribute to cognitive deficits in schizophrenia, e.g., from genetic insults that weaken NMDAR transmission, or from blockade of NMDAR by kynurenic acid. Elevated levels of kynurenic acid in dlPFC may also contribute to cognitive deficits in other disorders with pronounced neuroinflammation (e.g., Alzheimer's disease), or peripheral infections where kynurenine can enter brain (e.g., delirium from sepsis, “brain fog” in COVID19). Much less is known about NMDAR actions in the primate cingulate cortices. However, NMDAR neurotransmission appears to process the affective and visceral responses to pain and other aversive experiences mediated by the cingulate cortices, which may contribute to sustained alterations in mood state. We hypothesize that the very rapid, antidepressant effects of intranasal ketamine may involve the disruption of NMDAR-generated aversive mood states by the anterior and subgenual cingulate cortices, providing a “foot in the door” to allow the subsequent return of top-down regulation by higher PFC areas. Thus, the detrimental vs. therapeutic effects of NMDAR blockade may be circuit dependent.https://www.frontiersin.org/articles/10.3389/fpsyt.2021.654322/fullNMDAR (NMDA receptor)prefrontal cortexcingulate cortexworking memorydepression |
| spellingShingle | Shengtao Yang Hyojung Seo Hyojung Seo Min Wang Amy F. T. Arnsten NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders Frontiers in Psychiatry NMDAR (NMDA receptor) prefrontal cortex cingulate cortex working memory depression |
| title | NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders |
| title_full | NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders |
| title_fullStr | NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders |
| title_full_unstemmed | NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders |
| title_short | NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders |
| title_sort | nmdar neurotransmission needed for persistent neuronal firing potential roles in mental disorders |
| topic | NMDAR (NMDA receptor) prefrontal cortex cingulate cortex working memory depression |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2021.654322/full |
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