Ketamine Modulates Theta and Gamma Oscillations

Neuroengineering Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia 19104, USA.
Journal of Cognitive Neuroscience (Impact Factor: 4.09). 08/2009; 22(7):1452-64. DOI: 10.1162/jocn.2009.21305
Source: PubMed


Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, has been studied as a model of schizophrenia when applied in subanesthetic doses. In EEG studies, ketamine affects sensory gating and alters the oscillatory characteristics of neuronal signals in a complex manner. We investigated the effects of ketamine on in vivo recordings from the CA3 region of mouse hippocampus referenced to the ipsilateral frontal sinus using a paired-click auditory gating paradigm. One issue of particular interest was elucidating the effect of ketamine on background network activity, poststimulus evoked and induced activity. We find that ketamine attenuates the theta frequency band in both background activity and in poststimulus evoked activity. Ketamine also disrupts a late, poststimulus theta power reduction seen in control recordings. In the gamma frequency range, ketamine enhances both background and evoked power, but decreases relative induced power. These findings support a role for NMDA receptors in mediating the balance between theta and gamma responses to sensory stimuli, with possible implications for dysfunction in schizophrenia.

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    • "Effects of NMDA receptor antagonists on LFP oscillations recorded in mice, which are also a widely used experimental animal, are less well investigated. In freely moving mice, ketamine has been shown to decrease the power of basal hippocampal theta (3–12 Hz) and increase gamma (30–80 Hz) power (Lazarewicz et al. 2010); however, effects on HFO remain largely unknown. A recent study demonstrated that administration of ketamine generated significantly higher cortical power in the HFO band in Sp4 hypomorphic mice (decreased expression of NR1 protein) compared with wild-type siblings (Ji et al. 2013). "
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    ABSTRACT: Rationale Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. Objective This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130–180 Hz) in mice. Methods Local field potentials were recorded from the nucleus accumbens of freely moving mice. Results Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT1A receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT2A, 5-HT7 and histamine H3 receptors had no effect. Conclusions NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT1A receptors.
    Full-text · Article · Oct 2015 · Psychopharmacology
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    • "Compared to P1, effects on P2 were more robust. Lastly, ketamine’s effects on qEEG have been well characterized previously and the current results are in line with these findings (86, 87). In addition, the dominant power of theta band is indicative of the strong hippocampal contribution to the vertex recorded EEG. "
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    ABSTRACT: Schizophrenia patients exhibit a decreased ability to detect change in their auditory environ-ment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detec-tion. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30 mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30 mg/kg) on deviance detection. Ketamine attenu-ated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant's N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia.
    Full-text · Article · Aug 2014 · Frontiers in Psychiatry
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    • "This and other evidence has led to the development of the NMDAr hypofunction hypothesis of schizophrenia, which posits that reduced activity at NMDA receptors leads to the expression of schizophrenia symptoms. We (Pinault, 2008; Hakami et al., 2009) and others (Ehrlichman et al., 2009; Lazarewicz et al., 2010) previously demonstrated that NMDAr antagonists dose-dependently increase the power of ongoing γ cortical oscillations in rodents and also recapitulate complex electrophysiological abnormalities seen in schizophrenia (Kulikova et al., 2012; Saunders et al., 2012). We further developed this model by examining the effects of antipsychotic compounds on ongoing γ oscillations, and in response to a ketamine challenge (Jones et al., 2012). "
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    ABSTRACT: Noncompetitive N-methyl-d-aspartate receptor (NMDAr) antagonists can elicit many of the symptoms observed in schizophrenia in healthy humans, and induce a behavioural phenotype in animals relevant to psychosis. These compounds also elevate the power and synchrony of gamma (γ) frequency (30-80 Hz) neural oscillations. Acute doses of antipsychotic medications have been shown to reduce ongoing γ power and to inhibit NMDAr antagonist-mediated psychosis-like behaviour in rodents. This study aimed to investigate how a chronic antipsychotic dosing regimen affects ongoing cortical γ oscillations, and the electrophysiological and behavioural responses induced by the NMDAr antagonist ketamine. Male Wistar rats were chronically treated with haloperidol (0.25 mg/kg/d), clozapine (5 mg/kg/d), LY379268 (0.3 mg/kg/d) or vehicle for 28 d, delivered by subcutaneous (s.c.) osmotic pumps. Weekly electrocorticogram (ECoG) recordings were acquired. On day 26, ketamine (5 mg/kg, s.c.) was administered, and ECoG and locomotor activity were simultaneously measured. These results were compared with data generated previously following acute treatment with these antipsychotics. Sustained and significant decreases in ongoing γ power were observed during chronic administration of haloperidol (64%) or clozapine (43%), but not of LY379268 (2% increase), compared with vehicle. Acute ketamine injection concurrently increased γ power and locomotor activity in vehicle-treated rats, and these effects were attenuated in rats chronically treated with all three antipsychotics. The ability of haloperidol or clozapine to inhibit ketamine-induced elevation in γ power was not observed following acute administration of these drugs. These results indicate that modulation of γ power may be a useful biomarker of chronic antipsychotic efficacy.
    Full-text · Article · Jun 2014 · The International Journal of Neuropsychopharmacology
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