Sleep-related thalamocortical spindles and delta oscillations are reduced during a ketamine-induced psychosis-relevant transition state

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. LAY ABSTRACT Schizophrenia is a chronic debilitating disease. Sleep disturbances associated with a reduction in spindles are observed as warning signs prior to the first psychotic episode. Every spindle is a short-lasting (~0.5 s) set of bioelectric sinusoidal waves at the frequency of 10-16 Hz generated within the thalamus. Sleep spindles, easily identifiable in a scalp electroencephalogram, occur hundreds of times during sleep and are implicated in cognition like memory processes. For this reason, spindles are seen as an electro-biomarker of the quality of sleep and cognitive performance. In patients at high risk of psychotic transition, the density (number/time unit) of spindles is reduced. The underlying mechanisms of this change are unknown. Glutamate-mediated neurotransmission in the thalamus plays a key role in the generation of spindles and the etiology of schizophrenia. Therefore, we tested the hypothesis that a reduced function of glutamate receptors at the thalamic level is involved in the psychosis-related reduction in spindles. Using cell-to-network neurophysiological methods in sleeping rats, we demonstrate that systemic administration of the NMDA glutamate receptor antagonist, ketamine, significantly decreases spindle density. This effect is consistently prevented by the widely used antipsychotic drug, clozapine. These original findings support the hypothesis of the involvement of a reduced function of NMDA glutamate receptors in the sleep spindle deficit observed in psychosis-related disorders. The present findings lay the foundation for the development of innovative therapies aimed at preventing psychotic, bipolar, and depressive disorders. HIGHLIGHTS Low-dose ketamine has a fast onset arousal promoting effect. Ketamine fleetingly reduces, in the first-/higher-order thalamocortical systems, sleep spindles and slow-waves, and amplifies gamma- and higher-frequency oscillations. Ketamine switches the firing pattern from a burst mode to a single action potential mode in both the glutamatergic thalamocortical neurons and the GABAergic thalamic reticular nucleus neurons. Ketamine strengthens the gamma-frequency band connectivity between thalamocortical and thalamic reticular nucleus neurons. The reference antipsychotic clozapine consistently prevents the ketamine effects.