NMDAR antagonist action in thalamus imposes delta oscillations on the hippocampus

Abstract

Work on schizophrenia demonstrates the involvement of the hippocampus in the disease and points specifically to hyperactivity of CA1. Many symptoms of schizophrenia can be mimicked by N-methyl-d-aspartate receptor (NMDAR) antagonist; notably, delta frequency oscillations in the awake state are enhanced in schizophrenia, an abnormality that can be mimicked by NMDAR antagonist action in the thalamus. Given that CA1 receives input from the nucleus reuniens of the thalamus, we sought to determine whether an NMDAR antagonist in the thalamus can affect hippocampal processes. We found that a systemic NMDAR antagonist (ketamine; 50 mg/kg) increased the firing rate of cells in the reuniens and CA1 in awake rats. Furthermore, ketamine increased the power of delta oscillations in both structures. The thalamic origin of the change in hippocampal properties was demonstrated in three ways: 1) oscillations in the two structures were coherent; 2) the hippocampal changes induced by systematic ketamine were reduced by thalamic injection of muscimol; and 3) the hippocampal changes could be induced by local injection of ketamine into the thalamus. Lower doses of ketamine (20 mg/kg) did not evoke delta oscillations but did increase hippocampal gamma power, an effect not dependent on the thalamus. There are thus at least two mechanisms for ketamine action on the hippocampus: a low-dose mechanism that affects gamma through a nonthalamic mechanism and a high-dose mechanism that increases CA1 activity and delta oscillations as a result of input from the thalamus. Both mechanisms may be important in producing symptoms of schizophrenia.

Interaction of nucleus reuniens and entorhinal cortex projections in hippocampal field CA1 of the rat

“…Since interneurons play important roles in the regulation of oscillations (Jonas et al 2004;Somogyi and Klausberger 2005;Klausberger 2009), it is noteworthy that low frequency (≤ 2 Hz) RE input is also able to drive interneurons in distal radiatum (Dolleman-van der Weel et al 1997) that inhibit both pyramidal cells and other inhibitory interneurons. Driving these particular radiatum interneurons may thus provide a possible mechanism for RE to impose a slow oscillation on CA1 cells, as previously reported by Zhang et al (2012). RE-induced oscillatory activity in CA1 may be in synchrony with slow oscillations in mPFC.…”

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

“…NMDA receptor channel blockers have additional neurophysiological effects, including induction of an increase in delta power (Dworak et al, 2011;Kiss et al, 2013;Zhang et al, 2012). In the present study, the higher doses of ketamine increased delta power both in the cortex and hippocampus during both drug-on and drug-off periods.…”

“…In the present study, the higher doses of ketamine increased delta power both in the cortex and hippocampus during both drug-on and drug-off periods. Mechanisms underlying changes in delta power are not fully understood; previous studies analyzed acute, short-time effects of ketamine on EEG, demonstrating a transient increase in delta power (Fu et al, 2008;Zhang et al, 2012). Therefore, late-onset increase in delta power could be a rebound effect in response to sleep deprivation induced acutely by administration of NMDA receptor antagonists (Kocsis, 2012b).…”

“…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.…”

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).…”