A comprehensive analysis of auditory event-related potentials and network oscillations in an NMDA receptor antagonist mouse model using a novel wireless recording technology

Abstract

There is growing evidence that impaired sensory processing significantly contributes to cognitive deficits found in schizophrenia. Electroencephalography (EEG) has become an important preclinical and clinical technique to investigate the underlying mechanisms of neurophysiological dysfunctions in psychiatric disorders. Patients with schizophrenia show marked deficits in auditory event-related potentials (ERP), the detection of deviant auditory stimuli (mismatch negativity, MMN), the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation (ASSR) and reduced auditory-evoked oscillation in the gamma range. Due to a novel data-logging technology (Neurologger, TSE Systems), it is now possible to record wireless EEG data in awake, free-moving small rodents without any restrictions due to size of the device or attached cables. Recently, a new version of the Neurologger was released with improved performance to record time-locked event-related EEG signals. In this study, we were able to show in mice that pharmacological intervention with the NMDA receptor antagonists Ketamine and MK-801 can impair a comprehensive selection of EEG/ERP readouts (ERP N1 amplitude, 40 Hz ASSR, basal and evoked gamma oscillation, MMN) and therefore mimic the EEG deficits observed in patients with schizophrenia. Our data support the translational value of NMDA receptor antagonists as a model for preclinical evaluation of sensory processing deficits relevant to schizophrenia. Further, the new Neurologger system is a suitable device for wireless recording of clinically relevant EEG biomarkers in freely moving mice and a robust translational tool to investigate novel therapeutic approaches regarding sensory processing deficits related to psychiatric disorders such as schizophrenia.

Keywords: Animal model; NMDA receptor antagonist; event-related potentials; gamma oscillation; schizophrenia; translational biomarker.

Figure 1

Experimental setup for auditory stimulation and EEG recording in a noise‐attenuated cubicle. IR (infrared) diodes that emit an infrared pulse time‐locked to the auditory stimulus are placed on the ceiling of the cubicle. The loudspeaker for presentation of auditory stimulation protocols is installed at the ceiling of the cubicle above the testing‐cage of the animal.

Figure 2

Different auditory stimulation protocols for (A) auditory event‐related potentials (ERP) and evoked oscillation recording (B) basal oscillation without auditory stimulation (C) Auditory steady‐state response (ASSR) recording and (D) mismatch negativity (MMN) recording.

Figure 3

Estimated differences and confidence limits at the significance level (confidence level γ = 0.95) on relevant comparisons based on mixed model for the different (A) N1 amplitude; (B) N1 gating; (C) basal gamma; (D) basal theta; (E) evoked gamma; (F) evoked theta; (G) ASSR power (H) ASSR ITC; (I) MMN. *Statistically significant after correction for multiple testing (applies only for the comparisons compound vs. vehicle). ^#Statistically significant at 5% level (applies only for the comparisons washout vs. vehicle).

Figure 4

Exemplary readouts for one individual animal before and after application of MK‐801 for (A) N1 amplitude; (B) basal gamma power; (C) evoked gamma power; (D) auditory steady‐state power; (E) auditory steady‐state intertrial coherence (ITC) and (F) mismatch negativity MMN (area under the curve).