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The hippocampus participates in a pharmacological rat model of absence seizures.

ABSTRACT: Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if 2.5-6 Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs.Local field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 area. In separate experiments, multiple unit recordings were made at the hippocampal CA1 pyramidal cell layer, or the mid-septotemporal hippocampus was inactivated by local infusion of GABAA receptor agonist muscimol.As PDs developed following GBL injection, coherence of local field potentials at 2.5-6 Hz increased between the hippocampus and thalamus, and between the hippocampus and the neocortex. Hippocampal theta rhythm was disrupted when GBL induced immobility in the rats. The probability of hippocampal multiple unit firing significantly increased at 40-80 ms prior to the negative peak of thalamic PDs. Coherence between hippocampal multiple unit activity and thalamic field potentials at 2.5-6 Hz was significantly increased after GBL injection. Muscimol infusion to inactivate the mid-septotemporal hippocampus, as compared to saline infusion, significantly decreased the peak frequency of the PDs induced by GBL, decreased 30-120 Hz hippocampal gamma power, and hastened the transition of PDs to 1-2 Hz slow waves.During GBL induced 2.5-6 Hz PDs, a hallmark of absence seizure, increased synchronization between the hippocampus and the thalamocortical network was indicated by frequency and temporal correlation analysis. These results suggest that the hippocampus was entrained by thalamocortical activity in the present model of absence seizures. Prolonged synchronization of the hippocampus may result in synaptic alterations that may explain the cognitive and memory deficits in some patients with absence seizures and absence status epilepticus.

SUBMITTER: Arcaro J

PROVIDER: S-EPMC4942264 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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The hippocampus participates in a pharmacological rat model of absence seizures.

Arcaro Justin J Ma Jingyi J Chu Liangwei L Kuo MinChing M Mirsattari Seyed M SM Stan Leung L L

Epilepsy research 20151224

<h4>Objective</h4>Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if 2.5-6 Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs.<h4>Methods</h4>Local field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 a ...[more]

PMID: 26773250

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Project description:BackgroundIn epilepsy, seizures are generated by abnormal synchronous activity in neurons. In the rat hippocampus (HIP), epileptiform activity has been found to be associated with gap junctions (GJs). GJs are formed by the combination of two hemichannels, each composed of six connexins. At low doses, the convulsive drug 4-aminopyridine (4-AP) produces epileptiform activity without affecting glutamate levels; therefore, GJs could participate in its effect. Based on this argument, in this study, the expression of Cx 32, Cx 36 and Cx 43 protein and mRNA in the HIP of rats treated with 4-AP was evaluated. The evaluation of connexins was carried out by chemifluorescent immunoassay, semiquantitative RT-PCR and immunofluorescence to detect the amount and distribution of connexins and of cellular markers in the HIP and dentate gyrus (DG) of animals treated with NaCl and 4-AP in the right entorhinal cortex. In these animals, convulsive behavior and EEG signals were analyzed.ResultsThe animals treated with 4-AP showed convulsive behavior and epileptiform activity 60 min after the administration. A significant increase in the protein expression of Cx 32, Cx 36 and Cx 43 was found in the HIP contralateral and ipsilateral to the site of 4-AP administration. A trend toward an increase in the mRNA of Cx 32 and Cx 43 was also found. An increase in the cellular density of Cx 32 and Cx 43 was found in the right HIP and DG, and an increase in the cellular density of oligodendrocytes in the DG and a decrease in the number of cells marked with NeuN were observed in the left HIP.ConclusionsCx 32 and Cx 43 associated with oligodendrocytes and astrocytes had an important role in the first stages of seizures induced by 4-AP, whereas Cx36 localized to neurons could be associated with later stages. Additionally, these results contribute to our understanding of the role of connexins in acute seizures and allow us to direct our efforts to other new anticonvulsant strategies for seizure treatment.

Project description:ObjectiveLow-frequency fiber-tract stimulation has been shown to be effective in treating mesial temporal lobe epilepsies through activation of the hippocampal commissure in rodents and human patients. The corpus callosum is a major pathway connecting the two hemispheres of the brain; however, few experiments have documented corpus callosum stimulation. The objective is to determine the efficacy of corpus callosum stimulation at low frequencies to suppress cortical seizures.Methods4-Aminopyridine was injected in the primary motor cortex of 24 rats under anesthesia. Recording electrodes were placed in the contralateral motor cortex and hippocampus. Three pairs of stimulating electrodes were inserted into the corpus callosum along its longitudinal axis. Local field potentials were recorded 1 hour before, during, and after stimulation to determine the effect of stimulation on seizure duration. Stimulation was delivered from each pair of electrodes independently in separate experiments. Furthermore, electrical stimulation was applied to the region of the corpus callosum with the highest degree of innervation of the seizure focus to compare the efficacy of different stimulation frequencies (1-30 Hz) on seizure suppression.ResultsCorpus callosum stimulation was effective at suppressing seizures at 10 Hz by 76% (P < 0.05, n = 5) and at 20 Hz by 95% (P < 0.0001, n = 14). Stimulation at frequencies of 1 and 30 Hz did not have a significant effect on reducing the total time spent seizing (P > 0.9999, n = 5). Furthermore, stimulation was only effective at suppressing seizures when the pair of electrodes was placed within the section of corpus callosum containing fibers innervating the seizure focus. Secondarily generalized seizures in the hippocampus were eliminated when seizures in the cortical focus were suppressed.SignificanceLow-frequency fiber-tract stimulation of the corpus callosum suppresses both cortical and cortically induced hippocampal seizures in an acute model of focal cortical seizures. The stimulation paradigm is selective, as it is only effective when targeted to specific regions of the corpus callosum that project maximally to cortical regions generating the seizure activity. Selective placement of stimulation electrodes along the corpus callosum could be used as a patient-specific treatment for cortical epilepsies.

Project description:Absence seizures-generalized rhythmic spike-and-wave discharges (SWDs) are the defining property of childhood (CAE) and juvenile (JAE) absence epilepsies. Such seizures are the most compelling examples of pathological neuronal hypersynchrony. All the absence detection algorithms proposed so far have been derived from the properties of individual SWDs. In this work, we investigate EEG phase synchronization in patients with CAE/JAE and healthy subjects to explore the possibility of using the wavelet phase synchronization index to detect seizures and quantify their disorganization (fragmentation). The overlap of the ictal and interictal probability density functions was high enough to preclude effective seizure detection based solely on changes in EEG synchronization. We used a machine learning classifier with the phase synchronization index (calculated for 1 s data segments with 0.5 s overlap) and the normalized amplitude as features to detect generalized SWDs. Using 19 channels (10-20 setup), we identified 99.2% of absences. However, the overlap of the segments classified as ictal with seizures was only 83%. The analysis showed that seizures were disorganized in approximately half of the 65 subjects. On average, generalized SWDs lasted about 80% of the duration of abnormal EEG activity. The disruption of the ictal rhythm can manifest itself as the disappearance of epileptic spikes (with high-amplitude delta waves persisting), transient cessation of epileptic discharges, or loss of global synchronization. The detector can analyze a real-time data stream. Its performance is good for a six-channel setup (Fp1, Fp2, F7, F8, O1, O2), which can be implemented as an unobtrusive EEG headband. False detections are rare for controls and young adults (0.03% and 0.02%, respectively). In patients, they are more frequent (0.5%), but in approximately 82% cases, classification errors are caused by short epileptiform discharges. Most importantly, the proposed detector can be applied to parts of EEG with abnormal EEG activity to quantitatively determine seizure fragmentation. This property is important because a previous study reported that the probability of disorganized discharges is eight times higher in JAE than in CAE. Future research must establish whether seizure properties (frequency, length, fragmentation, etc.) and clinical characteristics can help distinguish CAE and JAE.

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The hippocampus participates in a pharmacological rat model of absence seizures.

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The hippocampus participates in a pharmacological rat model of absence seizures.

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