NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia
Rationale: There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-04-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112000046 |
| _version_ | 1829492188797468672 |
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| author | John A. Saunders Michael J. Gandal Steve J. Siegel |
| author_facet | John A. Saunders Michael J. Gandal Steve J. Siegel |
| author_sort | John A. Saunders |
| collection | DOAJ |
| description | Rationale: There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently used pharmacological models of schizophrenia, recreate deficits in electrophysiological markers of disturbed brain circuits that are thought to underlie the illness. Furthermore, this study characterizes the specificity of these differences across the frequency spectrum so as to help identify the nature of selective circuit abnormalities that mediate each oscillatory response as relevant to schizophrenia. Design: Mouse EEG was recorded during exposure to repeated auditory stimuli after injection of either vehicle or drug. The dose–response relationship for each electrophysiological measure was determined for ketamine and MK-801. Time-frequency analyses were performed to assess baseline, total, and evoked power and intertrial coherence (ITC) at low (5–10 Hz) and high (35–80 Hz)-frequencies. Results: High frequency evoked and total power was decreased by MK-801 and ketamine in a dose-dependent fashion. High frequency baseline power was increased by MK-801 and ketamine in a dose-dependent fashion. Similar to evoked power, high frequency inter-trial coherence was dose-dependently decreased by both drugs. Low frequency ITC was only decreased by ketamine. Conclusions: Both ketamine and MK-801 cause alterations in high-frequency baseline (noise), total (signal), and evoked (signal) power resulting in a loss of high frequency SNR that is thought to primarily reflect local circuit activity. These changes indicate an inappropriate increase in baseline activity, which can also be interpreted as non-task related activity. Ketamine induced a loss of intertrial coherence at low frequencies, indicating a loss of consistency in low-frequency circuit mechanisms. As a proportion of baseline power, both drugs had a relative shift from low to high frequencies, reflecting a change in the balance of brain activity from coordination of global regions to a pattern of discoordinated, autonomous local activity. These changes are consistent with a pattern of fragmented regional brain activity seen in schizophrenia. |
| first_indexed | 2024-12-16T06:10:13Z |
| format | Article |
| id | doaj.art-9a3fc6af838349769fe120af253f0e6e |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T06:10:13Z |
| publishDate | 2012-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9a3fc6af838349769fe120af253f0e6e2022-12-21T22:41:25ZengElsevierNeurobiology of Disease1095-953X2012-04-0146193100NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophreniaJohn A. Saunders0Michael J. Gandal1Steve J. Siegel2Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA; Bioengineering Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USATranslational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USATranslational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA; Bioengineering Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA; Corresponding author at: Dept. of Psychiatry, University of Pennsylvania, Translational Research Laboratories, 125 S 31st St, Philadelphia, PA 19104, USA. Fax: +1 215 573 2041.Rationale: There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently used pharmacological models of schizophrenia, recreate deficits in electrophysiological markers of disturbed brain circuits that are thought to underlie the illness. Furthermore, this study characterizes the specificity of these differences across the frequency spectrum so as to help identify the nature of selective circuit abnormalities that mediate each oscillatory response as relevant to schizophrenia. Design: Mouse EEG was recorded during exposure to repeated auditory stimuli after injection of either vehicle or drug. The dose–response relationship for each electrophysiological measure was determined for ketamine and MK-801. Time-frequency analyses were performed to assess baseline, total, and evoked power and intertrial coherence (ITC) at low (5–10 Hz) and high (35–80 Hz)-frequencies. Results: High frequency evoked and total power was decreased by MK-801 and ketamine in a dose-dependent fashion. High frequency baseline power was increased by MK-801 and ketamine in a dose-dependent fashion. Similar to evoked power, high frequency inter-trial coherence was dose-dependently decreased by both drugs. Low frequency ITC was only decreased by ketamine. Conclusions: Both ketamine and MK-801 cause alterations in high-frequency baseline (noise), total (signal), and evoked (signal) power resulting in a loss of high frequency SNR that is thought to primarily reflect local circuit activity. These changes indicate an inappropriate increase in baseline activity, which can also be interpreted as non-task related activity. Ketamine induced a loss of intertrial coherence at low frequencies, indicating a loss of consistency in low-frequency circuit mechanisms. As a proportion of baseline power, both drugs had a relative shift from low to high frequencies, reflecting a change in the balance of brain activity from coordination of global regions to a pattern of discoordinated, autonomous local activity. These changes are consistent with a pattern of fragmented regional brain activity seen in schizophrenia.http://www.sciencedirect.com/science/article/pii/S0969996112000046SchizophreniaElectrophysiologyEndophenotypeAnimal modelsNMDA antagonist |
| spellingShingle | John A. Saunders Michael J. Gandal Steve J. Siegel NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia Neurobiology of Disease Schizophrenia Electrophysiology Endophenotype Animal models NMDA antagonist |
| title | NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia |
| title_full | NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia |
| title_fullStr | NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia |
| title_full_unstemmed | NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia |
| title_short | NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia |
| title_sort | nmda antagonists recreate signal to noise ratio and timing perturbations present in schizophrenia |
| topic | Schizophrenia Electrophysiology Endophenotype Animal models NMDA antagonist |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112000046 |
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