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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    • "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.
    Frontiers in Psychiatry 08/2014; 5. DOI:10.3389/fpsyt.2014.00096
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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.
    The International Journal of Neuropsychopharmacology 06/2014; 17(11):1-10. DOI:10.1017/S1461145714000959 · 4.01 Impact Factor
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    • "In addition, we and others have previously demonstrated that NMDAR antagonists , such as MK-801 and ketamine, recreate many of the electroencephalographic (EEG) frequency and event-related potential (ERP) abnormalities of schizophrenia (Connolly et al, 2004; Featherstone et al, 2012; Krystal et al, 1994; Lahti et al, 1995; Maxwell et al, 2006). These include reduced N1 amplitude, disruption of novelty-related mismatch negativity , as well as alterations in gamma oscillations (Ehrlichman et al, 2008; Lazarewicz et al, 2010). NMDAR antagonists also disrupt cognitive measures such as contextual fear conditioning and novel object recognition in rodents (Amann et al, 2009; Featherstone et al, 2012). "
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    ABSTRACT: NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative- symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox driven ablation of NR1 on PV-containing interneurons. Additionally, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-Methyl-6-(phenylethynyl) pyridine, MPEP). Data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability, while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated prior to and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggests that MPEP may be beneficial for core features of Autism Spectrum Disorders, current data suggest such effects require intact function of NMDAR on PV-interneurons.Neuropsychopharmacology accepted article preview online, 14 February 2014; doi:10.1038/npp.2014.7.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2014; 39(7). DOI:10.1038/npp.2014.7 · 7.05 Impact Factor
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