Effects of Nmda Receptor Antagonism on High Frequency Neuronal Oscillations and Working Memory Performance in Cynomolgus Macaques

Abstract

Disruptions in sensory processing and abnormal temporal integration of neuronal oscillations, especially within the gamma frequency range (30-80 Hz), have been identified in schizophrenic patients during working memory tasks and may contribute to the poor performance within this cognitive domain. Experimentally, alterations in gamma oscillations as well as the induction of other schizophrenia-like symptoms including cognitive deficits can be induced with NMDA receptor antagonists (e.g., phencyclidine [PCP], ketamine) in rodents, non-human primates (NHPs) and humans. Given that NHPs and humans have homologous prefrontal cortical structures that mediate attention and working memory processes, our objective was to characterize neuronal oscillations and event-related potentials (ERPs) to assess sensory and cognitive processing in cynomolgus macaques performing a delayed-match-to-sample (DMTS) working memory task. Macaques (n=7) were trained to match a sample stimulus following a delay period on a touchscreen in exchange for food rewards. Subsequently, all subjects were implanted with EEG electrodes [placed on the dura mater above the frontal cortex (FC) and primary visual cortex (V1)]. Thereafter, all animals received acute doses of PCP (0.03, 0.056, 0.1 mg/kg) or vehicle (Veh) and the effects on DMTS performance and EEG oscillations were measured. As compared to vehicle treatment, PCP produced a significant dose-dependent decrease in DMTS performance accuracy. EEG analysis during DMTS performance demonstrated that post-stimulus high gamma (51-80Hz) oscillations were significantly enhanced by PCP in the FC during correct responding. Moreover, PCP significantly elevated the amplitude of low gamma (30-50Hz), while suppressing alpha (8-12Hz) oscillations in FC. Similarly, in V1, PCP elevated both low and high gamma oscillations. Furthermore, PCP showed a significant post-stimulus enhancement in high gamma and reduction in beta (16-24Hz) bands during correct responding. In addition, PCP significantly prolonged the cognitively-relevant P300 component of the mean ERP during correct responses in FC but not in V1. Overall, our results suggest that acute administration of a NMDA receptor antagonist disrupts neuronal oscillations and cognitive processing, especially in the FC, and this may contribute to impaired cognitive performance in macaques. This study may help to define the role of high frequency oscillations in cognitive processes in higher order species, and to enhance our understanding of EEG recordings as a translatable biomarker for cognitive impairments associated with schizophrenia.