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.

Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population

“…As such, we propose that the reduced evoked gamma phenotype seen in patients is a relatively late stage manifestation of impaired NMDAR-mediated glutamate neurotransmission. Consistent with this hypothesis, Saunders et al assessed event-related gamma power using a dose-response administration of MK801, and found significant reductions in gamma, but only following relatively high doses of the drug, suggesting that this measure may also be relatively insensitive at detecting subtle reductions in glutamate function (Saunders et al, 2012a).…”

“…The lack of effect on either S1 amplitude on its attenuation is consistent with the finding that disruptions in these measures are typically observed only following relatively high doses of NMDA antagonists (de Bruin et al, 1999;Lazarewicz et al, 2010;Oranje et al, 2002;Saunders et al, 2012b;van Berckel et al, 1998). In contrast to the effects of the obligatory ERP, many researchers have reported reliable and substantial effects of NMDA antagonists on baseline and event-related gamma power (Featherstone et al, 2013;Jones et al, 2012;Kittelberger et al, 2012;Lazarewicz et al, 2010;Pinault, 2008;Saunders et al, 2012a). Similarly, homozygous constitutive reduction of NR1 (NR1−/−) produces significant reduction in evoked activity (Bodarky et al, 2009;Gandal et al, 2012b;Halene et al, 2009).…”

“…Such findings have led to a focus on the development of pharmacological methods that model these aspects of schizophrenia symptomology in laboratory animals. To date, several laboratories have demonstrated schizophrenia-like changes on a number of behavioral measures relevant to positive, negative, and cognitive symptoms in laboratory animals exposed to chronic NMDA antagonist administration (Ketamine, PCP or MK801) (Chan et al, 2008;Featherstone et al, 2012;Jentsch and Roth, 1999;Kittelberger et al, 2012;Lazarewicz et al, 2010;Neill et al, 2010;Rushforth et al, 2011;Saunders et al, 2012a;Siegel et al, 2003).…”

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

“…The PCP-induced suppression in P300 in the PC was also observed in healthy macaques and humans performing an auditory 'oddball' task following an acute subanesthetic dose of ketamine (Gil-da-Costa et al, 2013). Similarly in mice, prolongation of the N100 latency has been observed following acute administration of MK-801 (Saunders et al, 2012a) and in some (Ehrlichman et al, 2008), but not all (Maxwell et al, 2006), studies with ketamine using auditoryevoked paradigms.…”

Using an Automated 3D-tracking System to Record Individual and Shoals of Adult Zebrafish

“…However, it is worth mentioning that MK-801 has been found to induce social withdrawal 30 and reduce social investigative behaviors in rats 31 and has been studied as model for negative sumptomes of schizophrenia 30 . It also caused hyperactivity 31 , circling behavior 32 , sensory impairment 33 , and reduced prepulse inhibition 34 in mammals. Although we did not specifically test for those impairments, our findings seem to be consistent with them.…”