Seizure-Like Events in Disinhibited Ventral Slices of Adult Rat Hippocampus

Abstract

Borck, Cornelius and John G. R. Jefferys. Seizure-like events in disinhibited ventral slices of adult rat hippocampus. J. Neurophysiol. 82: 2130Neurophysiol. 82: -2142Neurophysiol. 82: , 1999. Epileptic discharges lasting 2-90 s, were studied in vitro in slices from the ventral hippocampus of adult rats, in which inhibition was blocked acutely with bicuculline methiodide (BMI, 5-30 M) and potassium ([K ϩ ] o ) raised to 5 mM. These seizure-like events (SLEs) comprised three distinct phases, called here primary, secondary, and tertiary bursts. Primary bursts lasted 90 -150 ms. Secondary bursts lasted a further 70 -250 ms, comprising a short series of afterdischarges riding on the same depolarization as the primary burst. Finally a train of tertiary bursts started with a peak frequency of 5-10 Hz and could last Ͼ1 min. Slices from the ventral hippocampus showed significantly higher susceptibility to SLEs than did dorsal slices. SLEs proved sensitive to ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. They were insensitive to N-methyl-D-aspartate (NMDA) receptor antagonists; 50 l D-2-amino-5-phosphonopentanoic acid (D-AP5) did block the transient secondary bursts selectively. SLEs were restricted to the hippocampus proper even if the entorhinal cortex was present. Entorhinal bursts could last Ͻ2 s and were only coupled with hippocampal bursts in a minority of slices. Reentry of epileptic bursts occasionally occurred during interictal discharges, but not during the later stages of SLEs. Full-length SLEs always started in CA3 region and could be recorded in minislices containing CA3 plus dentate hilus. Ion-sensitive microelectrodes revealed that interictal discharges were followed by short (2-3 s) [K ϩ ] o waves, peaking at ϳ7.5 mM. SLEs were always accompanied by increases in [K ϩ ] o reaching ϳ8.5 mM at the start of tertiary bursts; [K ϩ ] o then increased more slowly to a ceiling of 11-12 mM. After the end of each SLE, [K ϩ ] o fell back to baseline within 10 -15 s. SLEs were accompanied by significant increase in synaptic activity, compared with baseline and/or interictal activity, estimated by the variance of the intracellular signal in the absence of epileptic bursts and action potentials (0.38 mV 2 , compared with 0.13 mV 2 , and 0.1 mV 2 , respectively). No significant increases were observed in the interval preceding spontaneous interictal activity. These studies show that focal assemblies of hippocampal neurons, without long reentrant loops, are sufficient for the generation of SLEs. We propose that a key factor in the transition from interictal activity to SLEs is an increase in axonal and terminal excitability, resulting, at least in part, from elevations in [K ϩ ] o .

Prototypic Seizure Activity Driven by Mature Hippocampal Fast-Spiking Interneurons

“…Apparently, the generation of low-Ca 2ϩ -or GABA A -blockade-induced seizures never requires GABA-dependent synaptic transmissions among hippocampal neurons (Jefferys and Haas, 1982;Taylor and Dudek, 1982;Swann and Brady, 1984;Borck and Jefferys, 1999). The generation of 4-aminopyridine-induced seizures depends on glutamatergic synaptic excitations by the pyramidal cells (Avoli et al, 1993(Avoli et al, , 1996.…”

“…To explore the cellular mechanism underlying rhythm generation and synchronization in seizure (ictal) activity of temporal lobe epilepsy (McNamara, 1994), various experimental models using in vitro hippocampal preparations were developed by stimulating neurons electrically (Stasheff et al, 1985), altering the ionic composition of the extracellular environment [low Ca 2ϩ (Jefferys and Haas, 1982;Taylor and Dudek, 1982); low Mg 2ϩ (Anderson et al, 1986); high K ϩ (Traynelis and Dingledine, 1988)], and blocking potassium channels (4-aminopyridine) (Avoli et al, 1993) or GABA A receptors (Swann and Brady, 1984;Borck and Jefferys, 1999). Although fast GABAergic transmissions are apparently unnecessary for seizure expression under the low Ca 2ϩ or GABA A -blocking condition, it is quite possible that hippocampal GABAergic interneurons are involved in the expression of seizure-like activity in other models.…”

Adaptive electric field control of epileptic seizures

“…9A) is also interesting in light of other recent results. Although in some models CA3 can activate or sustain seizure-like events (Traynelis and Dingledine, 1988;Borck and Jefferys, 1999), it has been shown experimentally that the burst discharges arising from CA3 can suppress the development of seizure-like events in an in vitro preparation (Barbarosie and Avoli, 1997), and that delivering periodic stimulation in similar frequency ranges as the natural burst discharge rates can similarly suppress such epileptiform events (Bragdon et al, 1992;Jerger and Schiff, 1995;Barbarosie and Avoli, 1997). Evidence is accumulating that neuronal synchronization phenomena in the hippocampus may be limited by the rate of replacement of releasable excitatory transmitter (Staley et al, 1998).…”

Cortical epileptogenesis of slowly kindled freely moving rats

“…This change was already revealed in several, albeit in vitro, models of epilepsy that showed a marked inward current, with gradually increasing duration, preceding the start of the seizures [38,39]. Therefore the appearance of seizures might be a result of a longer depolarization that can be associated with pathological oscillations.…”