Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism.
A growing body of evidence indicates that neuronal oscillations in the gamma frequency range (30-80 Hz) are disturbed in schizophrenic patients during cognitive processes and may represent an endophenotype of the disease. N-methyl-D-aspartate (NMDA) receptor antagonists have been used experimentally to induce schizophrenia-like symptoms including cognitive deficits in animals and humans. Here we characterized neuronal oscillations and event-related potentials (ERPs) in Cynomolgus macaques fully trained to perform a continuous performance test (CPT) in the presence and absence of the NMDA antagonist phencyclidine (PCP). Macaques (n=8) were trained to touch 'target' stimuli and ignore 'distractor' stimuli presented randomly on a touchscreen. Subsequently, all subjects were implanted with epidural EEG electrodes over frontal (FC) and parietal cortices (PC) and later tested under vehicle (saline, i.m.) or acute PCP (0.1-0.3 mg/kg, i.m.) conditions. Compared with vehicle treatment, PCP produced a significant dose-dependent decrease in CPT performance accuracy and increased reaction times. Furthermore, PCP elevated the amplitudes of 'low' (30-50 Hz) and 'high' (51-80 Hz) gamma oscillations in FC and PC around target presentations for all correct responses. The CPT accuracy was inversely correlated with the gamma band amplitude in the presence of PCP. Additionally, PCP delayed the N100 peak latency in FC, and prolonged and suppressed the cognitively relevant P300 component of mean ERPs in FC and PC, respectively. The NMDA receptor antagonist-induced alteration in neuronal oscillations and ERPs may contribute to the observed cognitive deficits in macaques, and enhance our understanding of EEG recordings as a translatable biomarker.
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
Anushka V
AV
Goonawardena
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
Jaime
J
Heiss
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
Courtney
C
Glavis-Bloom
Neuroscience, Ophthalmology and Rare Diseases, F. Hoffmann-La Roche, Basel, Switzerland.
Gerhard
G
Trube
Neuroscience, Ophthalmology and Rare Diseases, F. Hoffmann-La Roche, Basel, Switzerland.
Edilio
E
Borroni
Neuroscience, Ophthalmology and Rare Diseases, F. Hoffmann-La Roche, Basel, Switzerland.
Daniela
D
Alberati
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
Tanya L
TL
Wallace
D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D065818:Gamma Rhythm / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D010296:Parietal Lobe / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000008:administration & dosage*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine