Differential Role of NR2A and NR2B Subunits in N-Methyl-D-Aspartate Receptor Antagonist-Induced Aberrant Cortical Gamma Oscillations

Abstract

Background NMDA receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in human and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast firing interneurons. These neurons are critical for gamma oscillations indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis. Methods Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n=5; NVP-AAM077, n=18), NR2B-selective (ifenprodil, n=6; threo-ifenprodil, n=4; Ro25–6985, n=13), and NR2C/D-selective (PPDA, n=8) antagonists, along with vehicle and non-selective NMDA-R antagonists (ketamine, n=10, MK801, n=12). Changes in prepulse inhibition of startle was tested after MK-801(n=6), NVP-AAM077, and Ro-6891 (n=5) injection. Results Strong increase in gamma power was induced by non-selective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects. Conclusions Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

“…The resulting hyperglutamatergic state is believed to mediate the enhanced field gamma activity by stimulating kainate and AMPA receptor-mediated activation of the cortical interneuron-pyramidal cell network (McNally et al, 2011;Roopun et al, 2008). Indeed, a robust increase in field gamma oscillations is one of the most consistent findings in response to systemic treatment with NMDA antagonists (Hakami et al, 2009;Kocsis, 2012;Sebban et al, 2002).…”

“…To understand whether the induced gamma is a mere reflection of the elevation in baseline gamma activity that NMDA antagonists are well known to engender (Hakami et al, 2009;Kocsis, 2012;Sebban et al, 2002), we compared induced power through duration of train stimulation with the total gamma band power at the beginning of each epoch when there was no auditory stimulation. We found a highly significant positive correlation (Pearson's r) and no statistical difference between the two measures (paired t-test; data not shown) under all treatment conditions, suggesting that induced power in our paradigm was merely reflecting the gamma power present in the signal.…”

GluN2D N-Methyl-D-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia

“…NMDARs are tetrameric complexes composed of two GluN1 subunits and two subunits from among the GluN2A-D and GluN3A-B subunits (Ikeda et al, 1992;Ishii et al, 1993;Mishina et al, 1993;Monyer et al, 1994;Traynelis et al, 2010). Pharmacologic studies in vivo have indicated a predominant role for GluN2A subunits in NMDAR antagonist-induced neuronal oscillations (Kocsis, 2012). However, in vitro experiments suggest a greater role for GluN2B subunits (McNally et al, 2011), and the role of GluN2C and GluN2D subunits is unclear.…”

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…The neurophysiological changes caused by acute administration of ketamine and believed to be associated with the psychotomimetic effects are broadly described (Hong et al, 2010;Javitt et al, 2008Javitt et al, , 2012Kocsis, 2012a;Kocsis et al, 2013). In contrast, neurophysiological mechanisms that may underlie the antidepressive effects of ketamine are much less explored.…”

“…Acute administration of ketamine impairs auditory gating, increases delta power and elicits aberrant, high-power gamma oscillation in rats (Kocsis, 2012a;Pinault, 2008;Zhang et al, 2012) and humans (Kocsis et al, 2013). We investigated whether CP-101,606 had acute neurophysiological effects similar to ketamine in an identical recording paradigm.…”