A single psychotomimetic dose of ketamine decreases thalamocortical spindles and delta oscillations in the sedated rat

Abstract

Background: In schizophrenia, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the psychosis-related spindle deficit.Methods: An electrophysiological multisite cell-to-network exploration was used to investigate, in sleeping rats, the effects of a ketamine-induced psychosis-relevant transition state in the sensorimotor and associative/cognitive thalamocortical (TC) systems.Results: Under the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4Hz) oscillations were recorded in the EEG of the frontoparietal cortex, in thalamic extracellular recordings (n=16), in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons (n=8), and in intracellularly recorded TC neurons (n=8). The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700 Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity (n=11). The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta-and gamma-/higher-frequency TC oscillations (n=7). Conclusion:The present findings support the hypothesis that NMDA receptor hypofunction is involved in the psychosis-related reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion (from burst to single APs) of ongoing TC-TRN activities may have involved both the ascending reticular activating system and the corticothalamic pathway.

Network asynchrony underlying increased broadband gamma power

“…Increased spontaneous broadband gamma oscillations have also been demonstrated in other mouse models of PV neuron dysfunctions (del Pino et al, 2013;Cho et al, 2015), and in individuals with schizophrenia (Mathalon and Sohal, 2015;Grent-'t-Jong et al, 2018). Further, administration of NMDAR antagonists such as ketamine (Pinault, 2008;Hakami et al, 2009;Kulikova et al, 2012;Caixeta et al, 2013;Picard et al, 2019;Lopes-Aguiar et al, 2020;Mahdavi et al, 2020;McNally et al, 2020), or MK-801 (Carlén et al, 2012;Molina et al, 2014;Hudson et al, 2020), is associated with increased power in spontaneous broadband gamma oscillations in both anesthetized and awake rodents, and also in humans (Rivolta et al, 2015). Importantly, lack of NMDAR in PV neurons blunts this response (Carlén et al, 2012;Picard et al, 2019;Hudson et al, 2020), confirming that cortical PV interneurons are a central target of NMDAR antagonists.…”

Transcranial Bipolar Direct Current Stimulation of the Frontoparietal Cortex Reduces Ketamine-Induced Oscillopathies: A Pilot Study in the Sedated Rat

“…Our objective being to set up a bipolar FP tDCS capable of reducing or normalizing the effects of ketamine on spontaneously-occurring neuronal oscillations, all the results presented in the following were obtained in the ketamine condition, that is, after a single subcutaneous administration of ketamine at a subanesthetic and psychotomimetic dose (2.5 mg/kg) [19]. It is worth reminding that, in the sedated rat, ketamine fleetingly decreases the power of spindles (sigma-frequency oscillations) and increases that of broadband gamma oscillations with a peak effect 15-20 minutes after its systemic administration [24]. A partial or total recovery is usually observed 60-80 minutes later.…”

“…1B1, B2), it would make sense to conclude that the efficacy of the tDCS on the controlateral spindle-like activities is secondary to the primary ipsilateral effects. Nevertheless, based on our previous data recorded under the same experimental conditions [24], it is questionable whether the late (~40 min after the ketamine administration) cortical activities were due either to a "true" stimulation effect (ketamine combined with tDCS +0.5 mA effects), or a spontaneous partial recovery (ketamine alone (tDCS 0 mA)). The present group data do not exclude an efficacy of the FP anodal tDCS paralleled with partial recovery.…”

“…Indeed, broadband gamma oscillations and spindles result from functional synaptic interactions between GABAergic and glutamatergic neurons. More specifically, gamma oscillations implicate such synaptic interactions in both the cortex and the thalamus [62,63]; sleep-related spindles are generated principally in the thalamus with synaptic interactions between the thalamic relay and reticular neurons [24,64]. So, when the EEG is synchronized, it predominantly displays delta oscillations and spindles, and the corresponding thalamic relay and reticular neurons mainly fire rhythmic high-frequency bursts of action potentials [64].…”

“…Furthermore, the ketamine-elicited gamma hyperactivity decreases the ability of cortico-thalamo-cortical networks to integrate incoming information [22,23]. In pentobarbital-sedated rats, ketamine transiently reduces the power of slow-wave oscillations and spindles by switching the firing pattern of both thalamic relay and reticular neurons from the burst mode to the single action potential mode [24]. Furthermore, clozapine, one of the most effective antipsychotic medications currently available, especially in treatment resistant patients with schizophrenia [25,26], prevents the ketamine effects on thalamocortical slow-wave oscillations and spindles [24].…”