vGLUT2 heterozygous mice show more susceptibility to clonic seizures induced by pentylenetetrazol.

Glutamate, the most abundant excitatory neurotransmitter in the central nervous system, is well known to be implicated in epileptic seizures. Therefore, impairments in glutamate transport could have an involvement in the mechanism of epileptogenesis. The uptake of glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (vGLUTs). There are three known vGLUT isoforms, vGLUT1-3. In this study, we are particularly interested in the vGLUT2 isoform. We investigated the possible role of vGLUT2 in pentylenetetrazol (PTZ)-induced seizure generation. Seizure threshold of PTZ was compared in vGLUT2 heterozygous knock out (HET) and wild type (WT) mice. In comparison with their WT littermates a lower dose of PTZ was needed in the vGLUT2 HET mice until the onset of the first myoclonic jerk. The threshold for PTZ-induced clonic seizure activity was also lower in the vGLUT2 HET mice. These results indicate, for the first time, that vGLUT2 is likely involved in the epileptogenesis of generalized seizures.

A comprehensive electrographic and behavioral analysis of generalized tonic-clonic seizures of GEPR-9s.

This study records noise-free intracerebral EEG of the genetically epilepsy prone rat (GEPR-9), along with behavioral correlates, during a seizure on unanesthetized freely behaving unrestrained animals. The GEPR-9 exhibits acoustically triggered generalized tonic-clonic seizures, and often times the EEG, recorded with conventional techniques, has resulted in data with imbedded movement artifact. For noise-free video-EEG recordings, we used a previously developed system that consists of a head connector with a FET preamplifier and battery, signal conditioning device (5000x gain, 1 Hz-100 Hz filters), A/D converter and video/PC-PC/video computer boards for recording image data. Each animal was implanted with three monopolar/referential electrodes chosen among the following areas: cortex, inferior colliculus, reticular formation and caudal medulla. The video-EEG data were quite similar for all recorded animals: (1) basal desynchronized EEG before sound stimulus; (2) increase in EEG frequency after stimulus and before seizure onset; (3) high-amplitude polyspikes during massive myoclonic thrusts with or without a very fast running episode; (4) an electrodecremental response during tonic extension; (5) wave and spike complex during forelimb and hindlimb tonic rigidity and posttonic clonus; (6) low-amplitude EEG during postictal depression. Time sequenced spectral analysis also highlights the epileptiform EEG pattern during seizure with high reproducibility between animals. While testing seizure naive GEPR-9s, there was a clear evolution from modest epileptiform EEG activity on the first acoustic stimulation to progressively higher amplitude, duration and frequency epileptiform EEG activity throughout seizure repetition.

Limbic epileptogenicity, cell loss and axonal reorganization induced by audiogenic and amygdala kindling in wistar audiogenic rats (WAR strain).

Audiogenic seizures are a model of generalized tonic-clonic brainstem-generated seizures. Repeated induction of audiogenic seizures, in audiogenic kindling (AuK) protocols, generates limbic epileptogenic activity. The present work evaluated associations between permanence of AuK-induced limbic epileptogenicity and changes in cell number/gluzinergic terminal reorganization in limbic structures in Wistar audiogenic rats (WARs). Additionally, we evaluated histological changes after only amygdala kindling (AmK) and only AuK, and longevity of permanence of AuK-induced limbic epileptogenicity, up to 160 days. WARs and Wistar non-susceptible rats were submitted to AuK (80 stimuli) followed by both 50 days without acoustic stimulation and AmK (16 stimuli), only AmK and only AuK. Cell counting and gluzinergic terminal reorganization were assessed, respectively, by using Nissl and neo-Timm histochemistries, 24 h after the last AmK stimulus. Evaluation of behavioral response to a single acoustic stimulus after AuK and up to 160 days without acoustic stimulation was done in another group. AuK-induced limbic epileptogenicity developed in parallel with a decrease in brainstem-type seizure severity during AuK. AmK was facilitated after AuK. Permanence of AuK-induced limbic epileptogenicity was associated with cell loss only in the rostral lateral nucleus of amygdala. Roughly 20 generalized limbic seizures induced by AuK were neither associated with hippocampal cell loss nor mossy fiber sprouting (MFS). AmK developed with cell loss in hippocampal and amygdala nuclei but not MFS. Main changes of gluzinergic terminals after kindling protocols were observed in amygdala, perirhinal and piriform cortices. AuK and AuK-AmK induced a similar number and type of seizures, higher than in AmK. AmK and AuK-AmK were associated with broader cell loss than AuK. Data indicate that permanent AuK-induced limbic epileptogenicity is mainly associated to gluzinergic terminal reorganization in amygdala but not in the hippocampus and with no hippocampal cell loss. Few AmK-induced seizures are associated to broader and higher cell loss than a higher number of AuK-induced seizures.

Tonic-clonic convulsions in meadow voles.

Some meadow voles (Microtus pennsylvanicus) exhibit prolonged tonic-clonic convulsions, possibly epileptiform seizures, when handled or exposed to a strange environment. These convulsions are often preceded by a period of slow head shaking and/or stiff-legged hopping, but never by the explosively wild running bouts that characterize convulsions in some mammals. Convulsions occasionally occur in meadow voles in response to mild disturbance, as when an individual in its home cage is carried from one room to another. In contrast, they can not be elicited by some of the auditory or olfactory insults used to induce epileptiform seizures in other mammals. Breeding experiments have established the genetic basis of the convulsions seen in meadow voles, and of particular interest here is the fact that some of the convulsing voles were caught in the wild. This raises the interesting possibility that wild voles in natural habitats might be susceptible to convulsions when startled.

Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice.

The effects of topiramate, a novel antiepileptic drug, on tonic and absence-like seizures in spontaneously epileptic rats (SER; zi/zi, tm/tm) and on sound-induced seizures in DBA/2 mice were investigated. Topiramate (20 and 40 mg/kg i.p.) inhibited both tonic and absence-like seizures in a dose-dependent manner, whereas phenytoin (20 mg/kg i.p.) and zonisamide (40 mg/kg i.p.) inhibited only the tonic seizures. The inhibitory effects of topiramate on absence-like seizures were antagonized by pretreatment with haloperidol (0.5 mg/kg i.p.), but those on the tonic seizures remained unaffected. Topiramate inhibited sound-induced seizures in DBA/2 mice (ED50 = 8.6 mg/kg p.o.). These findings suggest that topiramate may be effective for treatment of both convulsive and absence seizures of human epilepsy. The inhibitory effect of topiramate on absence-like seizures in SER may be mediated through the central dopaminergic system.