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 synchronised beta/gamma oscillations in a time window of a few hundred 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 anesthetised 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. The present findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system.

The N-Methyl d-Aspartate Glutamate Receptor Antagonist Ketamine Disrupts the Functional State of the Corticothalamic Pathway.

The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in cortical and subcortical structures, including the thalamus. The underlying mechanisms are unknown. The goal of the present study was to determine whether a ketamine-induced psychotic-relevant state disturbs the functional state of the corticothalamic (CT) pathway. Multisite field recordings were performed in the somatosensory CT system of the sedated rat. Baseline activity was challenged by activation of vibrissa-related prethalamic inputs. The sensory-evoked thalamic response was characterized by a short-latency (∼4 ms) prethalamic-mediated negative sharp potential and a longer latency (∼10 ms) CT-mediated negative potential. Following a single subcutaneous injection of ketamine (2.5 mg/kg), spontaneously occurring and sensory-evoked thalamic gamma oscillations increased and decreased in power, respectively. The power of the sensory-related gamma oscillations was positively correlated with both the amplitude and the area under the curve of the corresponding CT potential but not with the prethalamic potential. The present results show that the layer VI CT pathway significantly contributes in thalamic gamma oscillations, and they support the hypothesis that reduced NMDAR activation disturbs the functional state of CT and corticocortical networks.

HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models.

OBJECTIVE: Evidence from animal and human studies indicates that epilepsy can affect cardiac function, although the molecular basis of this remains poorly understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate pacemaker activity and modulate cellular excitability in the brain and heart, with altered expression and function associated with epilepsy and cardiomyopathies. Whether HCN expression is altered in the heart in association with epilepsy has not been investigated previously. We studied cardiac electrophysiologic properties and HCN channel subunit expression in rat models of genetic generalized epilepsy (Genetic Absence Epilepsy Rats from Strasbourg, GAERS) and acquired temporal lobe epilepsy (post-status epilepticus SE). We hypothesized that the development of epilepsy is associated with altered cardiac electrophysiologic function and altered cardiac HCN channel expression. METHODS: Electrocardiography studies were recorded in vivo in rats and in vitro in isolated hearts. Cardiac HCN channel messenger RNA (mRNA) and protein expression were measured using quantitative PCR and Western blotting respectively. RESULTS: Cardiac electrophysiology was significantly altered in adult GAERS, with slower heart rate, shorter QRS duration, longer QTc interval, and greater standard deviation of RR intervals compared to control rats. In the post-SE model, we observed similar interictal changes in several of these parameters, and we also observed consistent and striking bradycardia associated with the onset of ictal activity. Molecular analysis demonstrated significant reductions in cardiac HCN2 mRNA and protein expression in both models, providing a molecular correlate of these electrophysiologic abnormalities. SIGNIFICANCE: These results demonstrate that ion channelopathies and cardiac dysfunction can develop as a secondary consequence of chronic epilepsy, which may have relevance for the pathophysiology of cardiac dysfunction in patients with epilepsy.

Acute effect of carbamazepine on corticothalamic 5-9-Hz and thalamocortical spindle (10-16-Hz) oscillations in the rat.

A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)-thalamocortical (TC) network, more specifically on CT 5-9-Hz and TC spindle (10-16-Hz) oscillations. Two to three successive 5-9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5-9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5-9-Hz depolarizing wave-hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately -70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5-9-Hz waves can trigger TC spindles.

Enduring Effects of Early Life Stress on Firing Patterns of Hippocampal and Thalamocortical Neurons in Rats: Implications for Limbic Epilepsy.

Early life stress results in an enduring vulnerability to kindling-induced epileptogenesis in rats, but the underlying mechanisms are not well understood. Recent studies indicate the involvement of thalamocortical neuronal circuits in the progression of kindling epileptogenesis. Therefore, we sought to determine in vivo the effects of early life stress and amygdala kindling on the firing pattern of hippocampus as well as thalamic and cortical neurons. Eight week old male Wistar rats, previously exposed to maternal separation (MS) early life stress or early handling (EH), underwent amygdala kindling (or sham kindling). Once fully kindled, in vivo juxtacellular recordings in hippocampal, thalamic and cortical regions were performed under neuroleptic analgesia. In the thalamic reticular nucleus cells both kindling and MS independently lowered firing frequency and enhanced burst firing. Further, burst firing in the thalamic reticular nucleus was significantly increased in kindled MS rats compared to kindled EH rats (p<0.05). In addition, MS enhanced burst firing of hippocampal pyramidal neurons. Following a stimulation-induced seizure, somatosensory cortical neurons exhibited a more pronounced increase in burst firing in MS rats than in EH rats. These data demonstrate changes in firing patterns in thalamocortical and hippocampal regions resulting from both MS and amygdala kindling, which may reflect cellular changes underlying the enhanced vulnerability to kindling in rats that have been exposed to early life stress.

Opposite effects of ketamine and deep brain stimulation on rat thalamocortical information processing.

Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in γ frequency (30-80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomofunctional mechanisms remain elusive. Clinical and experimental evidence suggests that these deficits result from a hyporegulation of glutamate N-methyl-D-aspartate receptors. Here we modeled these deficits in rats with ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore, we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high-frequency electrical stimulation (HFS) of the thalamus. A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensory-evoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders.

Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy.

Aberrant function of pacemaker currents (Ih), carried by hyperpolarization-activated cation non-selective (HCN) channels, affects neuronal excitability and accompanies epilepsy, but its distinct roles in epileptogenesis and chronic epilepsy are unclear. We probed Ih function and subunit composition during both pre- and chronically epileptic stages in thalamocortical (TC) neurones of the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Voltage gating of Ih was unaltered in mature somatosensory TC cells, both in vivo and in vitro. However, the enhancement of Ih by phasic, near-physiological, cAMP pulses was diminished by approximately 40% and the half-maximal cAMP concentration increased by approximately 5-fold. This decreased responsiveness of Ih to its major cellular modulator preceded epilepsy onset in GAERS, persisted throughout the chronic state, and was accompanied by an enhanced expression of the cAMP-insensitive HCN1 channel mRNA (> 50%), without changes in the mRNA levels of HCN2 and HCN4. To assess for alterations in TC cell excitability, we monitored the slow up-regulation of Ih that is induced by Ca2+-triggered cAMP synthesis and important for terminating in vitro synchronized oscillations. Remarkably, repetitive rebound Ca2+ spikes evoked normal slow Ih up-regulation in mature GAERS neurones; that sufficed to attenuate spontaneous rhythmic burst discharges. These adaptive mechanisms occurred upstream of cAMP turnover and involved enhanced intracellular Ca2+ accumulation upon repetitive low-threshold Ca2+ discharges. Therefore, HCN channels appear to play a dual role in epilepsy. Weakened cAMP binding to HCN channels precedes, and likely promotes, epileptogenesis in GAERS, whereas compensatory mechanisms stabilizing Ih function contribute to the termination of spike-and-wave discharges in chronic epilepsy.

Cellular interactions in the rat somatosensory thalamocortical system during normal and epileptic 5-9 Hz oscillations.

In Genetic Absence Epilepsy Rats from Strasbourg (GAERS), generalized spike-and-wave (SW) discharges (5-9 SW s(-1)) develop during quiet immobile wakefulness from a natural, medium-voltage, 5-9 Hz rhythm. This study examines the spatio-temporal dynamics of cellular interactions in the somatosensory thalamocortical system underlying the generation of normal and epileptic 5-9 Hz oscillations. Paired single-unit and multi-unit recordings between the principal elements of this circuit and intracellular recordings of thalamic, relay and reticular, neurones were conducted in neuroleptanalgesied GAERS and control, non-epileptic, rats. The identity of the recorded neurones was established following juxtacellular or intracellular marking. At least six major findings have emerged from this study. (1) In GAERS, generalized spike-and-wave discharges were correlated with synchronous rhythmic firings in related thalamic relay and reticular neurones. (2) Usually, corticothalamic discharges phase-led related relay and reticular firings. (3) A depolarizing wave emerging from a barrage of EPSPs was the cause of both relay and reticular discharges. (4) In some relay cells, which had a relatively high membrane input resistance, the depolarizing wave had the shape of a ramp, which could trigger a low-threshold Ca2+ spike. (5) In reticular cells, the EPSP barrage could further trigger voltage-dependent depolarizations. (6) The epilepsy-related thalamic, relay and reticular, intracellular activities were similar to the normal-related thalamic activities. Overall, these findings strongly suggest that, during absence seizures, corticothalamic neurones play a primary role in the synchronized excitation of thalamic relay and reticular neurones. The present study further suggests that absence-related spike-and-wave discharges correspond to hypersynchronous wake-related physiological oscillations.