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

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.

Positive Allosteric Modulation of AMPA Receptors from Efficacy to Toxicity: The Interspecies Exposure-Response Continuum of the Novel Potentiator PF-4778574

“…The objective of this study was to quantify the effects of systemically administered PF-4778574 on the cortical disruption of electroencephalogram (EEG) and paired-pulse facilitation (PPF) by the noncompetitive NMDAR antagonist MK-801 in urethaneanesthetized Sprague-Dawley rats (Kiss et al, 2011b). This is a preclinical model, which evaluates the subiculum-medial PFC pathway, proposed for studying NMDAR hypofunction of schizophrenia.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…However, a 4-week treatment reversed the magnitude of LTP to control level. Intrathalamic administration of MK-801 changes local field potentials and paired-pulse facilitation in rats, indicative of changes in short-term plasticity (Kiss et al, 2011). After application of MK-801, homosynaptic LTP of the direct cortical input to CA1 was abolished for at least 1 week, with partial recovery after 4 weeks (Wöhrl et al, 2007).…”

Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions

“…Several studies have shown that the PFC and MD are the predominant sites mediating the actions of non-competitive NMDAR antagonists, including changes in neurotransmission and behaviour (Amargós-Bosch et al 2006;López-Gil et al 2007;Kargieman et al 2007;Zhang et al 2009Zhang et al , 2012Santana et al 2011;Kiss et al 2011;López Hill and Scorza 2012). Furthermore, it has been proposed that PCP acts on the cortico-thalamo-cortical circuit involving the PFC, RS 15 and thalamus (Celada et al 2013).…”

“…There are, however, some differences in the degree of PCP-induced c-Fos-IR in these regions -suggesting that different mechanisms might contribute to the effects of PCP, or that the primary PCP-mediated activation is at an afferent site that projects stronger to the VLO and RS than the mPFC. Studies have shown that whereas systemic administration of non-competitive NMDAR antagonists leads to PFC and MD hyperactivity, locally injected antagonists in the PFC has no effect on the activity of PFC neurons (Suzuki et al 2002;Jodo et al 2005;Kiss et al 2011) suggesting excitatory inputs to the PFC to be involved in the actions of non-competitive NMDAR antagonists. Further, local MK-801 administration into the MD produces effects similar to systemically injected MK-801 (Kiss et al 2011) indicating that non-competitive NMDAR antagonists act on circuit level at thalamic areas.…”

“…Another important aspect to take into account is that also subcortical areas are relevant for PCP-or MK-801-mediated changes in activity and neurotransmission (Suzuki et al 2002;Jodo et al 2005;Amargós-Bosch et al 2006;López-Gil et al 2007). Several studies point to the mediodorsal and centromedial thalamic nuclei, that are reciprocally connected to the PFC (Berendse and Groenewegen, 1991;Fuster, 2008), to be of major importance in mediating the effects of non-competitive NMDAR antagonists (Kargieman et al 2007;Santana et al 2011;Kiss et al 2011;Celada et al 2013). …”