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

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.

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Highlights

► Low dose MK-801 creates EEG endophenotypes similar to autism ► At the highest doses tested, these changes overlap with schizophrenia findings ► These findings illustrate the relative amount of NMDAR dysfunction in the two disorders

Keywords

• Autism, electrophysiology, endophenotype, animal models, NMDA receptor antagonist

• John Saunders^{a, b},
• Michael J. Gandal^{a, b},
• Timothy P. Roberts^{b, c},
• Steve J. Siegel^{a, b, ,}

• ^a Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104
• ^b Bioengineering Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104
• ^c Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104

• http://dx.doi.org/10.1016/j.bbr.2012.06.032, How to Cite or Link Using DOI

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Corresponding author. Dept. of Psychiatry, University of Pennsylvania, Translational Research Laboratories, 125 S 31st St, Philadelphia, PA 19104, Tel.: +215 573 0278, fax: +215 573 2041.

Fuente: http://www.sciencedirect.com/science/article/pii/S0166432812004457