Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia
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We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dysregulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism.
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Monkeys performing SZ-relevant cognitive task exhibit reduced synchronous firing and disrupted connectivity in PFC neurons after NMDAR antagonist administration.
“In agreement with this, monkeys performing a SZ-relevant cognitive task exhibit the reduced synchronous firing and disrupted connectivity in PFC neurons after the administration of an NMDAR antagonist 175.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [175]
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Crowe, D. A., Willow, A., Blackman, R. K., DeNicola, A. L., Chafee, M. V., & Amirikian, B. R. (2023) · eLife · doi:10.7554/elife.79352 · Cited by 4 · see citing works
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Neural Computations Underpinning Anxiety in Health and Disease
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Abnormal Low-Gamma Small-World Response After Visual Stimulation in SchizophreniaPreprint
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Computational Modeling in Various Cognitive Fields
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Computational Modeling in Psychiatry
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Effects of ketamine on frontoparietal interactions during working memory in macaque monkeysPreprint
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Neural circuits and processes of working memory
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A circuit dissection of perception–action decoupling in S-ketamine-induced hallucination-like states
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- Authors
- Zick, J. L., Blackman, R. K., Crowe, D. A., Amirikian, B., DeNicola, A. L., Netoff, T. I., & Chafee, M. V.
- Affiliations
- University of Minnesota (US)
- Augsburg University (US)
- Corresponding author
- Chafee, Matthew V.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 98
- Issue
- 6
- Pages
- 1243-1255.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6085178
- OpenAlex
- W2805153744
- Cited by
- 50
- References
- 72
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 4 · 2023: 9 · 2022: 6 · 2021: 13 · 2020: 5 · 2019: 5
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH077779, R01MH107491, 5F30MH108205-02, R25 MH101076, F31MH109238)
- National Institute of General Medical Sciences (T32 GM008244, T32GM847121)
- Wilfred Wetzel Graduate Fellowship
- Minnesota Medical Foundation
- Winston and Maxine Wallin Neuroscience Discovery Fund
- MnDrive Neuromodulation Fellowship
- American Brain Sciences Chair
- Department of Veterans Affairs
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- NMDA receptor, phencyclidine, schizophrenia, prefrontal cortex, spike timing, spike synchronization, effective connectivity, transfer entropy, cognitive control deficits
- MeSH terms
- Action Potentials, Animals, Cognition, Cortical Synchronization, Macaca mulatta, Neural Pathways, Neurons, Phencyclidine, Schizophrenia, Task Performance and Analysis, Time Factors, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Excitatory Amino Acid Antagonists, Executive Function
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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