N-methyl-d-aspartic acid receptor antagonist–induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia

Ehrlichman, Richard S.; Gandal, Michael J.; Maxwell, Christina R.; Lazarewicz, Maciej T.; Finkel, Leif H.; Contreras, Diego; Turetsky, Bruce I.; Siegel, Steven J.

doi:10.1016/j.neuroscience.2008.10.031

Cited by 164 publications

(137 citation statements)

References 64 publications

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“…Consistent with this scenario, MK-801 has been shown to increase glutamate levels in the prefrontal cortex of rats (Moghaddam et al, 1997), while decreasing GABA levels (Yonezawa et al, 1998). The data we report here along with others (Ehrlichman et al, 2009a;Hakami et al, 2009;Lazarewicz et al, 2010Pinault, 2008 indicate that acute NMDAR antagonists produce robust elevations in gamma band activity. It is hypothesized that NMDAR antagonists may preferentially act at certain subtypes of GABAergic neurons to produce alterations in gamma activity.…”

Section: Discussionsupporting

confidence: 89%

Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism

Sullivan

Timi

Hong

et al. 2014

Neuropsychopharmacol

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Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. In this study we developed a tool to record skull EEG in awake-behaving rats in a similar manner to how human EEG are obtained and then used this technique to test whether acute NMDA receptor antagonism alters rodent EEG signals in a similar manner as in humans. Acute MK-801 treatment elevated gamma power and reduced beta band power, which closely mirrored EEG data from healthy volunteers receiving acute ketamine. To explore the mechanisms behind these oscillatory changes, we examined the effects of GABA-A receptor blockade, finding that picrotoxin (PTX) recapitulated the decrease in sound-evoked beta oscillations observed with acute MK-801, but did not produce changes in gamma band power. Chronic treatment with either PTX or MK-801 did not affect frequency-specific oscillatory activity when tested 24 h after the last drug injection, but decreased total broadband oscillatory power. Overall, this study validated a novel platform for recording rodent EEG and demonstrated similar oscillatory changes after acute NMDA receptor antagonism in both humans and rodents, suggesting that skull EEG may be a powerful tool for further translational studies.

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Section: Discussionsupporting

confidence: 89%

Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism

Sullivan

Timi

Hong

et al. 2014

Neuropsychopharmacol

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“…Using fMRI, we have shown that ketamine causes complex temporal and regional blood oxygen level-dependent changes, including hypoactivation and hyperactivation with the prefrontal and parietal cortices preferentially affected (79). This is in line with EEG studies that have demonstrated increases in highfrequency and decreases in low-frequency neural oscillations in humans (80) and in mice (81). In addition, resting-state positron emission tomography studies have demonstrated that ketamine-induced increase in regional blood flow is counterintuitively associated with reduced oxygen extraction (82,83), possibly related to the direct vascular effect of ketamine (84).…”

Section: P100 Effectsupporting

confidence: 85%

Effects of Acute Ketamine Infusion on Visual Working Memory: Event-Related Potentials

Koychev

Deakin

El‐Deredy

et al. 2017

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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This is the accepted version of the paper.This version of the publication may differ from the final published version. ABSTRACT BACKGROUND: Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia. METHODS: Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task. RESULTS: Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group. CONCLUSIONS: We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade. Permanent repository link

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“…In our study, the effect on 'high' gamma following PCP administration is consistent with EEG and magnetoencephalography results reported in healthy volunteers receiving acute ketamine (Hong et al, 2010;Rivolta et al, 2015), as well as with in vivo local field potentials and EEG recordings following the administration of NMDA receptor antagonists to rodents (Ehrlichman et al, 2009;Pinault, 2008;Lazarewicz et al, 2010;Sullivan et al, 2015). The enhancement in gamma oscillations following acute NMDA receptor inhibition could result from at least two separate mechanisms in which the NMDA receptor antagonist: (i) acts directly on PV-containing GABAergic interneurons and thereby disinhibits pyramidal cells (eg, layer 5 of dlPFC); or (ii) acts directly on pyramidal cells causing a reduction in glutamate release which in turn reduces the stimulation of AMPA receptors on GABAergic interneurons which may also transiently disinhibit pyramidal cells for example in layer 3 of dlPFC (Rotaru et al, 2011;Wang et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

“…However, the elevation in pre-stimulus baseline gamma amplitude was inversely associated with accuracy in the CPT, and we observed a similar inverse correlation with the poststimulus gamma response and accuracy. These data may suggest an inappropriate increase in non-task related activity that negatively impacts overall performance, and are similar to findings of elevated gamma following the acute administration of NMDAR antagonists that have been reported in rodents (Ehrlichman et al, 2009;Saunders et al, 2012b) and humans (Hong et al, 2010) in auditory-evoked stimulus paradigms.…”

Section: Discussionsupporting

confidence: 86%

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

Goonawardena

Heiss

Glavis-Bloom

et al. 2015

Neuropsychopharmacol

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A growing body of evidence indicates that neuronal oscillations in the gamma frequency range are disturbed in schizophrenic patients during cognitive processes and may represent an endophenotype of the disease. N-methyl-D-aspartate (NMDA) receptor antagonists have been used experimentally to induce schizophrenia-like symptoms including cognitive deficits in animals and humans. Here we characterized neuronal oscillations and event-related potentials (ERPs) in Cynomolgus macaques fully trained to perform a continuous performance test (CPT) in the presence and absence of the NMDA antagonist phencyclidine (PCP). Macaques (n = 8) were trained to touch 'target' stimuli and ignore 'distractor' stimuli presented randomly on a touchscreen. Subsequently, all subjects were implanted with epidural EEG electrodes over frontal (FC) and parietal cortices (PC) and later tested under vehicle (saline, i.m.) or acute PCP (0.1-0.3 mg/ kg, i.m.) conditions. Compared with vehicle treatment, PCP produced a significant dose-dependent decrease in CPT performance accuracy and increased reaction times. Furthermore, PCP elevated the amplitudes of 'low' (30-50 Hz) and 'high' (51-80 Hz) gamma oscillations in FC and PC around target presentations for all correct responses. The CPT accuracy was inversely correlated with the gamma band amplitude in the presence of PCP. Additionally, PCP delayed the N100 peak latency in FC, and prolonged and suppressed the cognitively relevant P300 component of mean ERPs in FC and PC, respectively. The NMDA receptor antagonist-induced alteration in neuronal oscillations and ERPs may contribute to the observed cognitive deficits in macaques, and enhance our understanding of EEG recordings as a translatable biomarker.

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N-methyl-d-aspartic acid receptor antagonist–induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia

Cited by 164 publications

References 64 publications

Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism

Reverse Translation of Clinical Electrophysiological Biomarkers in Behaving Rodents under Acute and Chronic NMDA Receptor Antagonism

Effects of Acute Ketamine Infusion on Visual Working Memory: Event-Related Potentials

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

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