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

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          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.

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          Abnormal neural oscillations and synchrony in schizophrenia.

          Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.
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            A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior

            Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.
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              Cognitive functions of gamma-band activity: memory match and utilization.

              Oscillatory neural activity in the gamma frequency range (>30Hz) has been shown to accompany a wide variety of cognitive processes. So far, there has been limited success in assigning a unitary basic function to these oscillations, and critics have raised the argument that they could just be an epiphenomenon of neural processing. We propose a new framework that relates gamma oscillations observed in human, as well as in animal, experiments to two underlying processes: the comparison of memory contents with stimulus-related information and the utilization of signals derived from this comparison. This model attempts to explain early gamma-band responses in terms of the match between bottom-up and top-down information. Furthermore, it assumes that late gamma-band activity reflects the readout and utilization of the information resulting from this match.
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                Author and article information

                Contributors
                niklas.schuelert@boehringer-ingelheim.com
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                28 August 2018
                August 2018
                : 6
                : 16 ( doiID: 10.1002/phy2.2018.6.issue-16 )
                : e13782
                Affiliations
                [ 1 ] CNS Diseases Research Germany Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss Germany
                [ 2 ] Biostatistics and Data Sciences Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss Germany
                Author notes
                [*] [* ] Correspondence

                Niklas Schuelert, CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.

                Tel: +49‐0‐73515496041

                Fax: +49‐0‐7351545128

                E‐mail: niklas.schuelert@ 123456boehringer-ingelheim.com

                Article
                PHY213782
                10.14814/phy2.13782
                6113138
                30155997
                3a2ff67b-aef7-4f2d-afd6-9c00881481e8
                © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 February 2018
                : 25 May 2018
                Page count
                Figures: 4, Tables: 0, Pages: 18, Words: 11754
                Categories
                Cognitive and Behavioural Neuroscience
                Neurological Conditions, Disorders and Treatments
                Sensory Neuroscience
                Original Research
                Original Research
                Custom metadata
                2.0
                phy213782
                August 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:28.08.2018

                animal model,event‐related potentials,gamma oscillation,nmda receptor antagonist,schizophrenia,translational biomarker

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