Article

Ketamine modulates theta and gamma oscillations

Neuroengineering Laboratory, Department of Bioengineering, University of Pennsylvania, Philadelphia 19104, USA.
Journal of Cognitive Neuroscience (Impact Factor: 4.69). 08/2009; 22(7):1452-64. DOI: 10.1162/jocn.2009.21305
Source: PubMed

ABSTRACT 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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Available from: Steven J Siegel, Aug 12, 2015
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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 · 5.26 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 · 7.83 Impact Factor
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    • "Adolescence is marked by developmental change in brain structure and neurotransmitter function that may be susceptible to the effects of chronic ketamine exposure. Gamma oscillations are strongly regulated by both GABA and glutamate systems (Carlen et al., 2011; Ehrlichman et al., 2009; Gandal et al., 2012; Gonzalez- Burgos et al., 2011; Lazarewicz et al., 2010; Lewis et al., 2004, 2005; Uhlhaas and Singer, 2010) and these systems undergo marked transformation during the adolescent period (Behrens and Sejnowski, 2009; Huppe-Gourgues and O'Donnell, 2012; Tseng and O'Donnell, 2005; Wang and Gao, 2009). Several recent reports have shown that event-related gamma power responses to both auditory and visual stimuli increase during the adolescent period (Rojas et al., 2006; Uhlhaas et al., 2009; Uhlhaas and Singer, 2011; Werkle-Bergner et al., 2009), raising the possibility that changes in event-related gamma could serve as an important biomarker of neurodevelopmental milestones and cognitive development. "
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    ABSTRACT: Increased susceptibility to cognitive impairment or psychosis in adulthood is associated with adolescent drug abuse. Studies in adults have identified impairments in attention and memory, and changes in EEG, as common consequences of ketamine abuse. In contrast, the effects of ketamine on the juvenile brain have not been extensively tested. This is a significant omission, since abuse of ketamine is often observed within this age group. Juvenile mice (4-6 weeks of age) were administered ketamine (20mg/kg) for 14 days. EEG was assessed in response to auditory stimulation both at one week following ketamine exposure at 7 weeks of age (juvenile) and again at 12 weeks of age (adult). EEG was analyzed for baseline activity, event-related power and event-related potentials (ERPs). While no effects of ketamine exposure were observed during the juvenile period, significant reductions in amplitude of the P20 ERP component and event-related gamma power were seen following ketamine when re-tested as adults. In contrast, reductions in event-related theta were seen in ketamine-exposed mice at both time points. Age related deficits in electrophysiological components such as P20 or event-related gamma may be due to an interruption of normal neural maturation. Reduction of NMDAR signaling during adolescence leads to delayed-onset disruption of gamma oscillations and the P20 component of the ERP. Further, delayed onset of impairment following adolescent ketamine abuse suggests that methods could be developed to detect and treat the early effects of drug exposure prior to the onset of disability.
    Drug and alcohol dependence 09/2013; 134. DOI:10.1016/j.drugalcdep.2013.09.017 · 3.28 Impact Factor
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