Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 234 (2), 233-7

NMDA Antagonist MK801 Recreates Auditory Electrophysiology Disruption Present in Autism and Other Neurodevelopmental Disorders

Affiliations

NMDA Antagonist MK801 Recreates Auditory Electrophysiology Disruption Present in Autism and Other Neurodevelopmental Disorders

John A Saunders et al. Behav Brain Res.

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.

Conflict of interest statement

Conflicts of interest

Steven Siegel reports having received grant support from Eli Lilly, AstraZeneca, NuPathe, and Pfizer that is unrelated to the content of this paper and consulting payments from NuPathe, Merck, Sanofi, and Wyeth that are unrelated to this work. Dr Roberts is a consultant for prism clinical imaging. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Column A represents the raw EEG trace for four epochs. In column B, a representative EEG trace filtered between 30 and 80 Hz is presented, showing the gamma present in the raw signal. In column C, the ERP from the previous raw animal data is shown with the P1 and N1 components marked. In column D, a group inter-trial coherence plot is shown for each drug dose.
Fig. 2
Fig. 2
N1 latency was examined following MK801 at 0.1, 0.2, 0.3, 0.4 mg/kg. There was a significant relationship between increasing MK801 dose and longer N1 latency (P < 0.0001, F(4,56) = 8.657). P1 latency was examined following MK801 at 0.1, 0.2, 0.3, 0.4 mg/kg. There was a significant relationship between increasing MK801 dose and longer P1 latency (P < 0.0001, F(4,56) = 9.855). This increase in P1 and N1 latency is similar to the pattern found for the corresponding M50 in children with language impairment using MEG [8,10]. Figure shows mean + SEM (*P < 0.05, **P < 0.01, ***P < 0.001 after Tukey’s test for multiple comparisons between saline and conditions).
Fig. 3
Fig. 3
Gamma ITC, evoked, and baseline power were examined following exposure to MK801 at 0.1, 0.2, 0.3, and 0.4 mg/kg. There was a significant relationship between increasing dose of MK801and reduction in gamma ITC and evoked power (gamma ITC: P < 0.001, F(4,56) = 5.738, gamma evoked power: P < 0.001, F(4,56) = 5.372). MK801 dose dependently increased gamma baseline power (P < 0.0001, F(4,56) = 13.15). Thus, MK801 recapitulates the overlapping pattern of reduced gamma ITC and evoked power along with increased gamma baseline power found among patients with either ASD or schizophrenia (Fig. 4). Figure shows mean + SEM (**P < 0.01, ***P < 0.01 after Tukey’s test for multiple comparisons between saline and conditions).
Fig. 4
Fig. 4
Graphical illustration of the continuum of EEG and behavioral deficits along different doses of MK801. The autism specific and overlapping with schizophrenia phenotypes are elucidated at the doses used in this study (1) [7] (2) [3,8] (3) [20] (4) [23] (5) [24] (6) [3] (7) [25] (8) [14].

Similar articles

See all similar articles

Cited by 20 PubMed Central articles

See all "Cited by" articles

Publication types

MeSH terms

Substances

Feedback