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Late deviance detection in rats is reduced, while early deviance detection is augmented by the NMDA receptor
L Harms1, W R Fulham2, J Todd3
1School of Psychology, University of Newcastle, Callaghan, NSW, Australia; Priority Centre for Brain and Mental Health Research, Callaghan, NSW, Australia; Hunter Medical Research Institute, Newcastle, NSW, Australia; Schizophrenia Research Institute, Randwick, NSW, Australia.
Abstract:
One of the most robust electrophysiological features of schizophrenia is reduced mismatch negativity, a component of the event related potential (ERP) induced by rare and unexpected stimuli in an otherwise regular pattern. Emerging evidence suggests that mismatch negativity (MMN) is not the only ERP index of deviance detection in the mammalian brain and that sensitivity to deviant sounds in a regular background can be observed at earlier latencies in both the human and rodent brain. Pharmacological studies in humans and rodents have previously found that MMN reductions similar to those seen in schizophrenia can be elicited by N-methyl-d-aspartate (NMDA) receptor antagonism, an observation in agreement with the hypothesised role of NMDA receptor hypofunction in schizophrenia pathogenesis. However, it is not known how NMDA receptor antagonism affects early deviance detection responses. Here, we show that NMDA antagonism impacts both early and late deviance detection responses. By recording EEG in awake, freely-moving rats in a drug-free condition and after varying doses of NMDA receptor antagonist MK-801, we found the hypothesised reduction of deviance detection for a late, negative potential (N55). However, the amplitude of an early component, P13, as well as deviance detection evident in the same component, were increased by NMDA receptor antagonism. These findings indicate that late deviance detection in rats is similar to human MMN, but the surprising effect of MK-801 in increasing ERP amplitudes as well as deviance detection at earlier latencies suggests that future studies in humans should examine ERPs over early latencies in schizophrenia and after NMDA antagonism.
Insights
NMDA receptor antagonism impacts early and late brain responses to unexpected sounds. While late deviance detection decreased, early auditory processing and deviance detection were unexpectedly enhanced by MK-801.
Area of Science:
- Neuroscience
- Electrophysiology
- Psychopharmacology
Background:
- Reduced mismatch negativity (MMN), an event-related potential (ERP), is a key electrophysiological finding in schizophrenia.
- NMDA receptor hypofunction is implicated in schizophrenia pathogenesis, with NMDA receptor antagonism mimicking MMN deficits.
- Early deviance detection, preceding MMN, is also observed in humans and rodents, but its modulation by NMDA antagonism is unknown.
Purpose of the Study:
- To investigate the effects of NMDA receptor antagonism on both early and late auditory deviance detection responses in rats.
- To determine if NMDA antagonism specifically affects early electrophysiological components related to sound change detection.
Main Methods:
- Electroencephalography (EEG) was recorded in awake, freely-moving rats.
- Rats were administered varying doses of the NMDA receptor antagonist MK-801.
- Deviance detection was assessed by comparing responses to standard and deviant auditory stimuli.
Main Results:
- NMDA antagonism, specifically MK-801, reduced the amplitude of a late deviance detection component (N55), consistent with MMN reductions.
- Unexpectedly, NMDA antagonism increased the amplitude of an early electrophysiological component (P13).
- Deviance detection at the earlier P13 latency was also enhanced by NMDA antagonism.
Conclusions:
- Late auditory deviance detection in rats shares similarities with human MMN.
- NMDA antagonism has differential effects on early and late deviance detection, increasing early ERP amplitudes and detection.
- Future human studies should explore early latency ERPs in schizophrenia and after NMDA antagonism.
