Translational Utility of the Mismatch Negativity: Implementing MMN in rats for Drug Discovery

1Translational EEG, PsychoGenics Inc., Tarrytown, NY, USA; 2Cadent Tx, Cambridge, MA, USA

Mismatch negativity (MMN) is a validated, objective measure of central auditory processing and has become a key clinical biomarker in schizophrenia and holds utility in other neuropsychiatric disorders. 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 40-60min following MK-801 treatment. Vehicle-treated rats had a significantly larger response to DEV than STD as measured by the N1 peak (between 20-60ms) and the area under the curve (AUC) for N1 (30-60ms) while the N1 and N1-AUC for STD and DEV did not differ after MK-801 (0.3 mg/kg), revealing clearly inhibited AEPs after NMDA antagonism. Further, the Difference Waves (DIFF), generated by subtracting STD from DEV, revealed MK-801 significantly suppressed both N1 and P2 (between 50-150ms) peak amplitudes and AUCs. Showing clear dose-dependency, MK-801 (0.1 mg/kg) had intermediate effects but did not demonstrate as robust an impairment of MMN as 0.3mg/kg. This work further validates that rats have a MMN correlate to that of the human and that this biomarker is dependent upon NMDA receptor function. Further, we demonstrate the ability to perform this in a higher-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.


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