NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders.

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TitleNMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders.
Publication TypeJournal Article
Year of Publication2012
AuthorsSaunders, JA, Gandal, MJ, Roberts, TP, Siegel, SJ
JournalBehav Brain Res
Volume234
Issue2
Pagination233-7
Date Published2012 Oct 01
ISSN1872-7549
KeywordsAnalysis of Variance, Animals, Autistic Disorder, Developmental Disabilities, Disease Models, Animal, Dizocilpine Maleate, Dose-Response Relationship, Drug, Electroencephalography, Electrophysiological Phenomena, Evoked Potentials, Auditory, Excitatory Amino Acid Antagonists, Male, Mice, Mice, Inbred C57BL, Reaction Time
Abstract

Autism is a highly disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors. There are few effective biological treatments for this disorder, partly due to the lack of translational biomarkers. However, recent data suggest that autism has reliable electrophysiological endophenotypes, along with evidence that some deficits may be caused by NMDA receptor (NMDAR) dysfunction. Similarly, the NMDAR antagonist MK801 has been used in behavioral animal models of autism. Since MK801 has also been used as a model of schizophrenia, this paper examines the independent and overlapping ways in which MK801 recreates the electrophysiogical changes present in both diseases. Mouse EEG was recorded in response to auditory stimuli after either vehicle or MK801 and the dose-response relationship for each measure was determined. ERP component amplitude and latency analysis was performed along with time-frequency analysis of gamma frequency inter-trial coherence and evoked power. Evoked gamma power and ITC were decreased by MK801 at the highest dose. P1, N1 latency and gamma baseline power were increased in dose dependent fashion following MK801. There were no amplitude changes in P1 or N1. MK801 caused alterations in evoked gamma activity, gamma ITC, gamma baseline power, P1 and N1 latency similar to findings in autism. These data provide evidence indicating that NMDAR dysfunction may contribute to deficits specific to autism and some that overlap with other disorders such as schizophrenia. Such observations could be important for developing novel therapeutics, as electrophysiological endophenotypes associate with functional measures and may provide early biomarkers for efficacy in clinical trials.

DOI10.1016/j.bbr.2012.06.032
Alternate JournalBehav. Brain Res.
PubMed ID22771812
PubMed Central IDPMC4124897
Grant ListP50 MH096891 / MH / NIMH NIH HHS / United States
R01 DC008871 / DC / NIDCD NIH HHS / United States
R01DC008871 / DC / NIDCD NIH HHS / United States
5R01DA023210-02 / DA / NIDA NIH HHS / United States
R01 DA023210 / DA / NIDA NIH HHS / United States
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