Dexmedetomidine, an alpha 2A receptor agonist, triggers seizures unilaterally in GAERS during the pre-epileptic phase: does the onset of spike-and-wave discharges occur in a focal manner?

IntroductionThe genetic absence epilepsy rat from Strasbourg (GAERS) is a rat model for infantile absence epilepsy with spike-and-wave discharges (SWDs). This study aimed to investigate the potential of alpha 2A agonism to induce seizures during the pre-epileptic period in GAERS rats.MethodsStereotaxic surgery was performed on male pups and adult GAERS rats to implant recording electrodes in the frontoparietal cortices (right/left) under anesthesia (PN23–26). Following the recovery period, pup GAERS rats were subjected to electroencephalography (EEG) recordings for 2 h. Before the injections, pup epileptiform activity was examined using baseline EEG data. Dexmedetomidine was acutely administered at 0.6 mg/kg to pup GAERS rats 2–3 days after the surgery and once during the post-natal (PN) days 25–29. Epileptiform activities before injections triggered unilateral SWDs and induced sleep durations, and power spectral density was evaluated based on EEG traces.ResultsThe most prominent finding of this study is that unilateral SWD-like activities were induced in 47% of the animals with the intraperitoneal dexmedetomidine injection. The baseline EEGs of pup GAERS rats had no SWDs as expected since they are in the pre-epileptic period but showed low-amplitude non-rhythmic epileptiform activity. There was no difference in the duration of epileptiform activities between the basal EEG groups and DEX-injected unilateral SWD-like-exhibiting and non-SWD-like activities groups; however, the sleep duration of the unilateral SWD-like-exhibiting group was shorter. Power spectrum density (PSD) results revealed that the 1.75-Hz power in the left hemisphere peaks significantly higher than in the right.DiscussionAs anticipated, pup GAERS rats in the pre-epileptic stage showed no SWDs. Nevertheless, they exhibited sporadic epileptiform activities. Specifically, dexmedetomidine induced SWD-like activities solely within the left hemisphere. These observations imply that absence seizures might originate unilaterally in the left cortex due to α2AAR agonism. Additional research is necessary to explore the precise cortical focal point of this activity

The Gamma-Butyrolactone Model of Absence Epilepsy: Acute and Chronic Effects in Wistar Rats

Objectives: We studied the electroencephalographic (EEG) and behavioral changes of the chemical model of generalized absence epilepsy induced by acute and chronic administration of gamma-butrolactone (GBL), a prodrug of gamma-hydroxybutyric acid.Methods: Adult male Wistar rats under anesthesia were implanted with bilateral cortical recording electrodes. The rats were administered 30 intraperitoneal injections of GBL twice daily from Monday to Friday and EEG was recorded 20 min before and 40 min after GBL injections. In order to monitor spontaneous spike-and-wave discharges (SWDs), the baseline EEGs on the subsequent Monday mornings after the first, second and third weekends were recorded for 90 min.Results: The intraperitoneal administration of GBL caused a rapid onset of bilaterally synchronous SWDs in the cortical EEG accompanied by behavioral immobility, vacant-staring and vibrissal twitching. By repeated GBL injections, animals displayed spontaneous bilateral synchronous SWDs in the baseline EEG on the Monday morning session after the GBL-free weekend period (60 h after the Friday afternoon injection).Conclusion: The present study reports the acute and chronic effects of the systemic administration of GBL. The chronic systemic application of GBL may represent a model of epileptogenesis for absence epilepsy

Surgical outcome of epilepsy patients evaluated with a noninvasive protocol

Surgery is now an accepted treatment for some medically intractable epilepsies. Presurgical evaluation is particularly important for the localization of the epileptogenic zone, which may necessitate sophisticated imaging techniques and intracranial electroencephalogram (EEG) recordings. If patients are carefully selected, however, successful results can be achieved with noninvasive evaluation methods. Seventy-seven patients were operated on for intractable seizures. All patients underwent EEG, neuropsychological, psychiatric, and magnetic resonance imaging investigations. Ictal EEG-video recording was performed in all nonlesional and in some lesional cases that had discordant data. Selective amygdalo-hippocampectomy was performed on patients with mesial temporal lobe epilepsy (MTLE), an extended or a limited lesionectomy was performed on patients with structural lesions, and a lesionectomy with deafferentation was performed on two patients with West syndrome. Electrocorticography was not used. Temporal lobe directed surgery was performed in 63.6% of the cases. The pathological examinations of all cases showed hippocampal sclerosis (HS) in 43%, tumor or tumor-like lesions in 36%, and cortical dysplasia in 5% of patients. After a mean follow-up of 17 months (range, 2-53), 75% of the patients were seizure-free with or without aura and 15% had a marked improvement, whereas 10% did not benefit from surgery. Neuropsychological outcome of patients with MTLE and I-IS also showed worthwhile results. Our patients, who were evaluated without pre- and perioperative intracranial recordings and other sophisticated techniques, had an outcome comparable to those in other series from more experienced centers. Our experience indicates that successful results, especially for patients with MTLE-HS and lesion-related epilepsies, can be obtained at centers with limited resources if the diagnoses and evaluation procedures are performed carefully

Do the quantitative relationships of synaptic junctions and terminals in the thalamus of genetic absence epilepsy rats from Strasbourg (GAERS) differ from those in normal control Wistar rats

Abnormal functional properties of the thalamocortical connections were reported in the absence of epilepsy. The present study compares the ratios of terminals (`RL'-round vesicles, large terminals, 'RS'-round vesicles, small terminals and 'F'-flattened vesicles) and synapse in three first-order (ventrobasal, lateral geniculate and anteroventral) and in three higher-order (posterior, lateral posterior and mediodorsal) thalamic nuclei of genetic absence epilepsy rats from Strasbourg (GAERS) with our earlier quantitative studies of normal Wistar rats to show whether quantitative differences were present in GAERS as compared to Wistar rat. Rats were perfused transcardially, the brains were removed and cut as 300 lmcoronal sections. Parts of the six thalamic nuclei were removed for routine electron microscopy and GABA immunocytochemistry. Twenty photographs from each section at 20,0009 magnification were taken, and the terminals were identified as RL, RS or F. (1) In normal Wistar rats (as in cats), the proportion of driver terminals (RL) and synapses is lower in higherorder than in first-order thalamic nuclei, but this difference is not present in GAERS animals. (2) The proportions of RS terminals and synapses for each thalamic nucleus showed no significant differences between GAERS and Wistar rats for any of the thalamic nuclei. (3) In GAERS, the proportion of inhibitory F terminals and synapses was significantly high in the VB and low in the LP thalamic nucleus. These abnormal ratios in the GAERS may be the cause of the spike-and-wave discharges of absence seizures or may represent a compensatory response of the thalamocortical circuitry to the absence seizures

Cerebellar connections: hypothalamus

Morphological studies have described reciprocal cerebello-hypothalamic projections in various species. These connections provide evidence for the key role of the cerebellum and hypothalamus in physiological regulatory processes such as autonomic and endocrine homeostasis. Our recent study using horseradish peroxidase (HRP) retrograde axonal transport technique showed cerebellar connections with the posterior and the dorsomedial hypothalamic nuclei. Further, we have demonstrated regional differences of the connections of the dorsomedial hypothalamic nucleus in rat. The results of HRP labelling showed that afferent pathways originating from the anterior and posterior parts of dorsomedial hypothalamic nucleus indicate a number of differences in the projections. The posterior part of the dorsomedial hypothalamic nucleus and the posterior hypothalamic nucleus receives direct distinct projections from the cerebellum, whereas the anterior part of the dorsomedial hypothalamic nucleus does not. Moreover, the posterior part of the dorsomedial nucleus of the hypothalamus when compared to the posterior hypothalamic nucleus has more intense connections with the cerebellum. These observations bring a new perspective on the question of how the cerebellum is involved in the regulation visceromotor functions

Participation of NMDA and kainate receptors of paraventricular nucleus in cardiovascular responses to glutamate receptor agonist

The nuclei of the hypothalamus have been shown to be involved in central cardiovascular homeostasis. Recent studies suggest that glutamate-containing neurons have an important role in the regulation of central cardiovascular function. We report first on the effects of intracerebrally injected NMDA and non-NMDA receptor ligands on blood pressure and heart rate in conscious Sprague-Dawley rats. In the second part, we describe the effect of blockade of NMDA or kainate receptors in the paraventricular nucleus on glutamate receptor agonist-induced blood pressure responses. Intracerebroventricular injections of L-glutamic acid, NMDA and kainic acid produced increases in mean arterial pressure. Kainic acid produced significant decreases in heart rate. Microinjection of DL-2-amino-5-phosphonopentanoic acid (APV; 25 and 50 nmol), a competitive NMDA receptor antagonist, into the paraventricular nucleus blunted the increases in the mean arterial pressure evoked by intracerebroventricular injections of NMDA (1 nmol), whereas microinjection of dinitroquinoxaline (DNQX; 20, 40 and 80 pmol), which acts as an antagonist at kainate receptors, failed to antagonize the cardiovascular effects of intracerebroventricular kainic acid (10 pmol). Microinjections of NMDA (100 pmol) into the paraventricular nucleus produced pressor responses, but kainic acid (5 and 10 pmol) failed to affect either mean arterial pressure or heart rate. These results suggest participation of the glutamergic system in cardiovascular regulation via NMDA receptors located within the paraventricular nucleus of the hypothalamus in rats

The effect of amygdala kindling on neuronal firing patterns in the lateral thalamus in the GAERS model of absence epilepsy

ObjectiveThe co-occurrence of absence and mesial temporal lobe epilepsy is rare in both humans and animal models. Consistent with this, rat models of absence epilepsy, including genetic absence epilepsy rats from Strasbourg (GAERS), are resistant to experimental temporal lobe epileptogenesis, in particular by amygdala kindling. Structures within the cortical-thalamocortical system are critically involved in the generation and maintenance of the electrographic spike-and-wave discharges (SWDs) that characterize absence seizures. Using in vivo electrophysiologic recordings, this study investigated the role of thalamocortical circuitry in the generalization of amygdala-kindling induced seizures in the GAERS and the nonepileptic control (NEC) strain of Wistar rats. MethodsGAERS and NEC rats were implanted with a stimulating electrode in amygdala and stimulated at afterdischarge threshold twice daily to a maximum number of 30 stimulations. Thereafter extracellular single neuron recordings were performed in vivo under neuroleptanesthesia in the thalamocortical network. ResultsIn NEC rats, amygdala kindling induced convulsive class V seizures and altered characteristics of neuronal activity in the thalamic reticular nucleus (TRN), in particular decreased firing rates and increased burst firing patterns. Less marked changes were seen in other regions examined: the ventroposteromedial nucleus of thalamus (VPM), the CA3 region of the hippocampus, and the deep layers (V/VI) of the cortex. GAERS did not progress beyond class II seizures, with a matched number of kindling stimulations, and the thalamic neuronal firing alterations observed in NEC rats were not seen. SignificanceThese data suggest that the TRN plays an important role in kindling resistance in GAERS and is central to the control of secondary generalization of limbic seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section