Mahdavi, A. | Search bioRxiv

bioRxiv2022

The psychotomimetic ketamine disrupts the transfer of late sensory information in the corticothalamic network

In prodromal and early schizophrenia, disorders of attention and perception are associated with structural and chemical brain abnormalities, and with dysfunctional corticothalamic networks exhibiting disturbed brain rhythms. The underlying mechanisms are elusive. The non-competitive NMDA receptor antagonist ketamine simulates the symptoms of prodromal and early schizophrenia, including disturbances in ongoing and task & sensory-related broadband beta-/gamma-frequency (17-29 Hz/30-80 Hz) oscillations in corticothalamic networks. In normal healthy subjects and rodents, complex integration processes, like sensory perception, induce transient, large-scale synchronized beta/gamma oscillations in a time window of a few hundreds of ms (200-700 ms) after the presentation of the object of attention (e.g., sensory stimulation). Our goal was to use an electrophysiological multisite network approach to investigate, in lightly anesthetized rats, the effects of a single psychotomimetic dose (2.5 mg/kg, subcutaneous) of ketamine on sensory stimulus-induced oscillations. Ketamine transiently increased the power of baseline beta/gamma oscillations and decreased sensory-induced beta/gamma oscillations. In addition, it disrupted information transferability in both the somatosensory thalamus and the related cortex and decreased the sensory-induced thalamocortical connectivity in the broadband gamma range. In conclusion, the present findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system. LAY ABSTRACTCognitive deficit is usual in schizophrenia. Perception- or task-related beta/gamma-frequency oscillations are decreased. In healthy humans and rodents, ketamine-induced NMDA receptor antagonism simulates the symptoms of early schizophrenia and excessively amplifies baseline beta/gamma oscillations. In the present study, using an electrophysiological multisite network approach in a rodent model, it is demonstrated that ketamine, systemically administered at a single psychotomimetic dose, increases baseline beta/gamma oscillations, decreases beta/gamma responses induced by sensory stimulation in a short time window (200-700 ms), and disrupts information transfer in the cortico-thalamo-cortical network. The present findings have mechanistic relevance for cognitive deficits in schizophrenia.

neuroscience↗

bioRxiv2019

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

BackgroundIn 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.\n\nMethodsAn 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.\n\nResultsUnder 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).\n\nConclusionThe 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.\n\nLAY ABSTRACTSchizophrenia 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.\n\nHIGHLIGHTSO_LILow-dose ketamine has a fast onset arousal promoting effect.\nC_LIO_LIKetamine fleetingly reduces, in the first-/higher-order thalamocortical systems, sleep spindles and slow-waves, and amplifies gamma- and higher-frequency oscillations.\nC_LIO_LIKetamine 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.\nC_LIO_LIKetamine strengthens the gamma-frequency band connectivity between thalamocortical and thalamic reticular nucleus neurons.\nC_LIO_LIThe reference antipsychotic clozapine consistently prevents the ketamine effects.\nC_LI

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