Abstract
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.
Highlights
The symptoms of schizophrenia are underlain by neuronal mechanisms that are poorly understood
The current experiments were conducted in freely moving rats to study the degree of correlation of changes in c power and locomotion in conscious rats treated with a single non-anesthetic dose of ketamine or MK-801 (Fig. 1)
2) that these pathophysiological c waves are not caused by conscious sensorimotor processing underlying hyperlocomotion-related brain state; 3) that the ECoG mainly reflects c oscillations recorded in intracortical networks; 4) that they occur all over the cerebral cortex and in multiple subcortical structures, including sensory, motor, limbic and associative/cognitive systems, and 5) that NMDA receptor (NMDAr) antagonist-induced ongoing c hyperactivities can be recorded under diverse consciousness states
Summary
The symptoms of schizophrenia are underlain by neuronal mechanisms that are poorly understood. The aim of the present study was to determine whether or not ketamine-induced aberrant cortical c oscillations were 1) correlated with quantitative measures of locomotion and 2) caused by conscious or unconscious premotor/ sensorimotor neuronal activity related to hyperlocomotion Answering these important questions allows the hypothesis that ‘‘NMDAr hypofunction-induced hyperlocomotion and/or aberrant ongoing c oscillations are associated to a psychotic-like state’’ to be tested. The 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 c (30–80 Hz) oscillations in the frontoparietal (sensorimotor) electrocorticogram (ECoG). This implied to explore the contribution of intracortical and subcortical networks in the generation of these pathophysiological ECoG c oscillations
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