BackgroundThe psychotomimetics ketamine and MK-801, non-competitive NMDA receptor (NMDAr) antagonists, induce cognitive impairment and aggravate schizophrenia symptoms. In conscious rats, they produce an abnormal behavior associated with a peculiar brain state characterized by increased synchronization in ongoing γ (30–80 Hz) oscillations in the frontoparietal (sensorimotor) electrocorticogram (ECoG). This study investigated whether NMDAr antagonists-induced aberrant γ oscillations are correlated with locomotion and dependent on hyperlocomotion-related sensorimotor processing. This also implied to explore the contribution of intracortical and subcortical networks in the generation of these pathophysiological ECoG γ oscillations.Methodology/Principal FindingsQuantitative locomotion data collected with a computer-assisted video tracking system in combination with ECoG revealed that ketamine and MK-801 induce highly correlated hyperlocomotion and aberrant γ oscillations. This abnormal γ hyperactivity was recorded over the frontal, parietal and occipital cortices. ECoG conducted under diverse consciousness states (with diverse anesthetics) revealed that NMDAr antagonists dramatically increase the power of basal γ oscillations. Paired ECoG and intracortical local field potential recordings showed that the ECoG mainly reflects γ oscillations recorded in underlying intracortical networks. In addition, multisite recordings revealed that NMDAr antagonists dramatically enhance the amount of ongoing γ oscillations in multiple cortical and subcortical structures, including the prefrontal cortex, accumbens, amygdala, basalis, hippocampus, striatum and thalamus.Conclusions/SignificanceNMDAr antagonists acutely produces, in the rodent CNS, generalized aberrant γ oscillations, which are not dependent on hyperlocomotion-related brain state or conscious sensorimotor processing. These findings suggest that NMDAr hypofunction-related generalized γ hypersynchronies represent an aberrant diffuse network noise, a potential electrophysiological correlate of a psychotic-like state. Such generalized noise might cause dysfunction of brain operations, including the impairments in cognition and sensorimotor integration seen in schizophrenia.

Opposite effects of ketamine and deep brain stimulation on rat thalamocortical information processing Sofya P Kulikova (1,2)*, Elena A Tolmacheva (1,2)**, Paul Anderson (1,2,3), Julien Gaudias (1,2)***, Brendan E Adams (1,2)****, Thomas Zheng (1,2,3), and Didier Pinault (1,2)(1) INSERM U666, physiopathologie et psychopathologie cognitive de la schizophrénie, Strasbourg, France. Abstract:Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in γ frequency (30-80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomo-functional mechanisms remain elusive. Clinical and experimental evidence suggest that these deficits result from a hyporegulation of glutamate N-Methyl d-Aspartate receptors (NMDAr). Here we modeled these deficits in rats with ketamine, a non-competitive NMDAr antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high-frequency electrical stimulation (HFS) of the thalamus.A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensoryevoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders. 3The anatomofunctional mechanisms of sensory and cognitive deficits in schizophrenia are unknown. These deficits are commonly associated with abnormal brain rhythms, including disturbances in γ frequency (30-80 Hz) oscillations (GFO) in corticocortical and thalamocortical (TC) circuits (Bokde et al., 2009;Clinton and Meador-Woodruff, 2004;de Haan W. et al., 2009;Friston, 2002;Herrmann and Demiralp, 2005;Light et al., 2006;Lisman, 2011;Meyer-Lindenberg, 2010;Pinault, 2011;Spencer et al., 2003;Uhlhaas and Singer, 2006). At least four types of GFO should be considered: 1) Spontaneously-occurring (baseline) GFO, which are dominant during desynchronized state of the electroencephalogram (Jasper, 1936;Sheer, 1975); 2) Sensory-evoked GFO, which are phase-locked to the stimulus onset (Pantev et al., 1991;Spencer et al., 2008b); 3) Steadystate GFO during r...