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.

Cortical Microcircuit Mechanisms of Mismatch Negativity and Its Underlying Subcomponents

“…An additional advantage presented by animal models is that virtually all experimental practices employed in human studies have homologs for animal experimentation, allowing for direct comparison while simultaneously offering more mechanistic insight. For instance, ketamine, along with another N-methyl-D-aspartate receptor (NMDAR) antagonists, is known to reduce the MMN in humans as well as rodents and non-human primates (Ehrlichman et al, 2008;Gil-Da-Costa et al, 2013;Chen et al, 2015;Haaf et al, 2018;Schuelert et al, 2018). Furthermore, the oddball task applies to a wide variety of experimental assays in animal research.…”

“…One point to consider in this problem is that NMDAR blockade, a face-valid model of SZ sensory processing features, also reduces MMN in humans and animals (Ehrlichman et al, 2008;Gil-Da-Costa et al, 2013;Haaf et al, 2018;Schuelert et al, 2018). The nature of how NMDAR blockade affects the time-course and oscillatory aspects of auditory MMN has led to the interpretation that DD specifically is NMDAR-dependent (Javitt et al, 1996;Lee et al, 2018).…”

Activation of group II metabotropic receptors attenuates cortical E-I imbalance in a 15q13.3 microdeletion mouse model

“…The technique used for the EEG recordings has been described in detail previously 26 . Briefly, for electrode implantation, animals were anaesthetized using isoflurane (2-3% in oxygen) and placed in a stereotaxic frame with a controlled heating blanket.…”

“…The setup specifications, the different stimulation protocols and the recording procedures for the 40 Hz ASSR EEG experiments are described in detail in 26 . Briefly, auditory stimuli were generated with an audio generator and presented via animals were given 30 min to acclimate to the apparatus prior to each recording session.…”

“…Data analysis was performed as described in 26 . The sampling rate of recording channels and trigger channels was set to 1000 Hz.…”