NMDA receptor hypofunction leads to generalized and persistent aberrant gamma oscillations independent of hyperlocomotion and the state of consciousness.

Abstract

BACKGROUND: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 gamma (30-80 Hz) oscillations in the frontoparietal (sensorimotor) electrocorticogram (ECoG). This study investigated whether NMDAr antagonists-induced aberrant gamma 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 gamma oscillations. METHODOLOGY/PRINCIPAL FINDINGS:Quantitative 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 gamma oscillations. This abnormal gamma 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 gamma oscillations. Paired ECoG and intracortical local field potential recordings showed that the ECoG mainly reflects gamma oscillations recorded in underlying intracortical networks. In addition, multisite recordings revealed that NMDAr antagonists dramatically enhance the amount of ongoing gamma oscillations in multiple cortical and subcortical structures, including the prefrontal cortex, accumbens, amygdala, basalis, hippocampus, striatum and thalamus. CONCLUSIONS/SIGNIFICANCE:NMDAr antagonists acutely produces, in the rodent CNS, generalized aberrant gamma oscillations, which are not dependent on hyperlocomotion-related brain state or conscious sensorimotor processing. These findings suggest that NMDAr hypofunction-related generalized gamma 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.