Progressive, potassium-sensitive epileptiform activity in hippocampal area CA3 of pilocarpine-treated rats with recurrent seizures

Abstract

Rat hippocampal area CA3 pyramidal cells synchronously discharge in rhythmic bursts of action potentials after acute disinhibition or convulsant treatment in vitro. These burst discharges resemble epileptiform activity, and are of interest because they may shed light on mechanisms underlying limbic seizures. However, few studies have examined CA3 burst discharges in an animal model of epilepsy, because a period of prolonged, severe seizures (status epilepticus) is often used to induce the epileptic state, which can lead to extensive neuronal loss in CA3. Therefore, the severity of pilocarpine-induced status epilepticus was decreased with anticonvulsant treatment to reduce damage. Rhythmic burst discharges were recorded in the majority of slices from these animals, between two weeks and nine months after status epilepticus. The incidence and amplitude of bursts progressively increased with time after status, even after spontaneous behavioral seizures had begun. The results suggest that modifying the pilocarpine models of temporal lobe epilepsy to reduce neuronal loss leads to robust network synchronization in area CA3. The finding that these bursts increase long after spontaneous behavioral seizures begin supports previous arguments that temporal lobe epilepsy exhibits progressive pathophysiology.

Increased gyrification and aberrant adult neurogenesis of the dentate gyrus in adult rats

“…In response to stimulation, burst discharges were elicited that were all-or-none, i.e., a burst discharge was produced or there was almost no response to stimulation. These data are consistent with the idea that the epileptiform burst discharges produced in hippocampal slices in response to disinhibition, elevated [K + ] o (or other conditions that favor epileptiform activity) are paroxysmal depolarization shifts (PDSs) that are all-or-none sudden, large depolarizations that initiate repetitive firing (Scharfman 1994a, b, 2015; Scharfman et al 1999; McCloskey and Scharfman 2011). …”

“…Epileptiform burst discharges were bursts of population spikes superimposed on a positive slow potential, corresponding to paroxysmal depolarization shifts in GCs (Rutecki et al 1985; Hwa et al 1991; Scharfman 1994a, b; Scharfman et al 1999; McCloskey and Scharfman 2011) and were evoked by an outer molecular layer stimulus approximately 300 μm away. The stimulating electrode (monopolar, Teflon-coated stainless steel wire, 75 μm wide including the Teflon; A&M Systems Inc.) was placed on the slice surface at the midpoint between the two recording sites (one at the peak of a gyrus and the other at a site adjacent to the gyrus).…”

Alzheimer‘s Disease and Epilepsy: Insight From Animal Models

“…Therefore, epileptogenesis and chronic epilepsy may involve gradual changes instead of sudden changes. The idea that a gradual emergence of epilepsy occurs in TLE has recently gathered more support because of detailed recordings from animals with epilepsy [36] or studies of epileptic rat hippocampus in brain slices [37–39]. For example, after SE in rats, it had been assumed that animals suddenly become epileptic after a prolonged period where epilepsy was absent but somehow developing in silence.…”

“…Moreover, indices of seizure susceptibility continue to become more severe after the first convulsive seizure even when studied ex vivo . For example, sensitivity of hippocampal area CA3 to elevated concentrations of extracellular potassium increases when slices are made from epileptic rats at longer and longer intervals after the first convulsive seizure [37]. …”

Prolonged seizures: what are the mechanisms that predispose or cease to be protective? A review of animal data

“…A causal relationship between disease progression and these changes is epistemologically impossible, but it is tempting to speculate that such prolonged changes are somehow involved in progression of seizure severity in animal models (McCloskey and Scharfman, ). Even beyond the discussion of the chicken and the egg, it is, however, improbable that any single mechanism is key to chronification of the epileptic condition, especially since studies so far have identified a large number of divergent mechanisms.…”