A Mahdavi1, Y Qin2, A-S Aubry3, D Cornec3, S Kulikova4, D Pinault5. 1. INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France.; University of Freiburg, Bernstein Center Freiburg, Germany. 2. INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France.; Netherlands Institute for Neuroscience, Amsterdam, the Netherlands. 3. INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France. 4. INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France.; National Research University Higher School of Economics, Perm, Russia. 5. INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France.. Electronic address: pinault@unistra.fr.
Abstract
BACKGROUND: In patients with psychotic disorders, 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 spindle deficit observed in schizophrenia. METHODS: An electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine 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 (1-4 Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. 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-(30-80 Hz) 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. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations. CONCLUSION: The present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway.
BACKGROUND: In patients with psychotic disorders, 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 spindle deficit observed in schizophrenia. METHODS: An electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine 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 (1-4 Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. 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-(30-80 Hz) 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. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations. CONCLUSION: The present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway.