S.C. LEISER1, D. BREGNA1, E. LEAHY1
1Translational EEG, PsychoGenics, Inc., Paramus, NJ, USA
Mismatch negativity (MMN) is a validated, objective measure of central auditory processing and has become a key clinical biomarker in schizophrenia. MMN is an auditory evoked potential (AEP) elicited clinically by an auditory oddball paradigm in which a different, deviant (‘oddball’; DEV) auditory (tonal) stimulus occurs infrequently and unexpectedly within a sequence of repetitive identical tonal stimuli (‘standards’, STD) and reflects pre-attentive processing dependent upon NMDA receptor function.
Here we demonstrate back-translatability of this AEP in Sprague-Dawley (SD) rats and show that NMDA receptor antagonism can impair rat MMN. First, we developed a system whereby we utilized the Data Sciences International (DSI) telemetry system to provide the flexibility and high-throughput nature of wireless recording up to 16 SD rats simultaneously in sound-attenuated chambers with the robust data handling and timestamping capabilities of the Cambridge Electronic Design (CED) micro1401 processor. A custom sequencer file enabled Spike2 software to generate tonal stimuli delivered to all rats simultaneously and timestamp the EEG data with digital precision. Rats were subjected to a standard oddball paradigm using 6kHz and 8kHz tones and assessed following MK-801 treatment.
Vehicle-treated rats had a significantly larger response to DEV than STD as measured by peak and area under the curve components of the AEP waveform, while MK-801 (0.1-0.3 mg/kg) showed dose-dependent effects on impairing MMN. Further, in a manner consistent with clinical literature, the NMDA-antagonist induced impairment of rat MMN can be recovered by agents acting via NMDA receptor modulation. Moreover, an important recent finding in our laboratory is that, similar to findings in humans, rat AEPs are modulated of across vigilance states (sleep-wake).
This work further validates that rats have a MMN correlate to that of the human MMN and that this biomarker is dependent upon similar mechanisms and receptor function. Further, we demonstrate the ability to perform this in a high-throughput manner necessary for drug discovery, which will lead to the further work needed to validate the translatability and predictive validity of the rat MMN.