Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice.
BACKGROUND
People with schizophrenia exhibit reduced ability to detect change in the auditory environment, which has been linked to abnormalities in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotransmission. This ability to detect changes in stimulus qualities can be measured with electroencephalography using auditory event-related potentials (ERPs). For example, reductions in the N100 and mismatch negativity (MMN), in response to pitch deviance, have been proposed as endophenotypes of schizophrenia. This study examines a novel rodent model of impaired pitch deviance detection in mice using the NMDA receptor antagonist ketamine.


METHODS
ERPs were recorded from unanesthetized mice during a pitch deviance paradigm prior to and following ketamine administration. First, N40 amplitude was evaluated using stimuli between 4 and 10 kHz to assess the amplitude of responses across the frequency range used. The amplitude and latency of the N40 were analyzed following standard (7 kHz) and deviant (5-9 kHz) stimuli. Additionally, we examined which portions of the ERP are selectively altered by pitch deviance to define possible regions for the mouse MMN.


RESULTS
Mice displayed increased N40 amplitude that was followed by a later negative component between 50 and 75 msec in response to deviant stimuli. Both the increased N40 and the late N40 negativity were attenuated by ketamine. Ketamine increased N40 latency for both standard and deviant stimuli alike.


CONCLUSIONS
The mouse N40 and a subsequent temporal region have deviance response properties similar to the human N100 and, possibly, MMN. Deviance responses were abolished by ketamine, suggesting that ketamine-induced changes in mice mimic deviance detection deficits in schizophrenia.
Ehrlichman
Richard S
RS
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Maxwell
Christina R
CR
Majumdar
Sonalee
S
Siegel
Steven J
SJ
D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001931:Brain Mapping; D003265:Contingent Negative Variation / Q000187:drug effects* / Q000502:physiology; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000187:drug effects* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005583:Fourier Analysis; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D010898:Pitch Perception / Q000502:physiology*; D011601:Psychophysics; D011930:Reaction Time / Q000502:physiology; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine