Role of Thalamic Projection in NMDA Receptor-Induced Disruption of Cortical Slow Oscillation and Short-Term Plasticity

Erik A Nilsen,Mihály Hajós,Thomas T Kawabe,Anthony J Milici,William E Hoffmann,Liam Scott,Tamás Kiss

doi:10.3389/fpsyt.2011.00014

Abstract

NMDA receptor (NMDAR) antagonists, such as phencyclidine, ketamine, or dizocilpine (MK-801) are commonly used in psychiatric drug discovery in order to model several symptoms of schizophrenia, including psychosis and impairments in working memory. In spite of the widespread use of NMDAR antagonists in preclinical and clinical studies, our understanding of the mode of action of these drugs on brain circuits and neuronal networks is still limited. In the present study spontaneous local field potential (LFP), multi- (MUA) and single-unit activity, and evoked potential, including paired-pulse facilitation (PPF) in response to electrical stimulation of the ipsilateral subiculum were carried out in the medial prefrontal cortex (mPFC) in urethane anesthetized rats. Systemic administration of MK-801 (0.05 mg/kg, i.v.) decreased overall MUA, with a diverse effect on single-unit activity, including increased, decreased, or unchanged firing, and in line with our previous findings shifted delta-frequency power of the LFP and disrupted PPF (Kiss et al., 2011). In order to provide further insight to the mechanisms of action of NMDAR antagonists, MK-801 was administered intracranially into the mPFC and mediodorsal nucleus of the thalamus (MD). Microinjections of MK-801, but not physiological saline, localized into the MD evoked changes in both LFP parameters and PPF similar to the effects of systemically administered MK-801. Local microinjection of MK-801 into the mPFC was without effect on these parameters. Our findings indicate that the primary site of the action of systemic administration of NMDAR antagonists is unlikely to be the cortex. We presume that multiple neuronal networks, involving thalamic nuclei contribute to disrupted behavior and cognition following NMDAR blockade.

Highlights

Schizophrenia has been linked to NMDA receptor (NMDAR) dysfunction by genetic, pharmacological, and imaging studies
3 Results In line with our previous experiments (Kiss et al, 2011) we have shown that in urethane anesthetized rats, spontaneous local field potential (LFP) recorded from the medial prefrontal cortex (mPFC) mainly consists of a large amplitude, regular, ≈2 Hz frequency oscillation termed high-delta (1.5–2.5 Hz band) oscillation (Figure 2)
4 Discussion The present findings demonstrate that systemic administration of the NMDAR antagonist MK-801 in anesthetized rats changes regular cortical field potential oscillation by altering power distribution within the delta band and modifies firing activity of the majority of cortical neurons

Summary

Introduction

Schizophrenia has been linked to NMDA receptor (NMDAR) dysfunction by genetic, pharmacological, and imaging studies. Abnormal glutamate metabolism has been reported in schizophrenic patients (Tsai et al, 1995), imaging studies have yielded conflicting results about brain glutamate levels. In support of the NMDAR dysfunction hypothesis of schizophrenia, NMDAR antagonists have been shown to produce psychosis and schizophrenia-like cognitive deficits (Krystal et al, 1994; Lahti et al, 1995b; Newcomer et al, 1999; Javitt et al, 2008) in healthy human subjects. Similar to responses seen in humans, NMDAR antagonist evoke sensory, behavioral, and cognitive disturbances in non-human primates (Taffe et al, 2002; Buccafusco and Terry, 2009; Roberts et al, 2010a,b,c), these pharmacological agents have become widely used to model various symptoms of schizophrenia in preclinical experiments. The precise mechanism and site of action of NMDAR antagonists still are not fully understood (for reviews see: Gunduz-Bruce, 2009; Gruber et al, 2010; Kantrowitz and Javitt, 2010; Marek et al, 2010)

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Results

Conclusion