Abstracts

The periodic discharge of the in vitro hippocampal CA3 pyramidal cell network is a well-studied model of pathological network synchronization. Many experimental manipulations that induce seizures in vivo also produce episodic depolarizations and bursts of action potentials of CA3. This synchronized bursting closely resembles interictal epileptiform activity recorded in vivo that underlies interictal spikes on the human electroencephalogram (EEG).
During conditions of high epileptiform activty in humans, such as periodic lateralized epileptiform discharges (PLEDS) or status epilepticus (SE), anticonvulsants that conventionally abort seizures may be ineffective. To study this phenomenon, we produced bursting in CA3 under conditions of [quot]high burst probability[quot], in which the burst frequency mimics PLEDs.
Valproic Acid (VPA) is used to treat status epilepticus. However, the underlying mechanisms of VPA remain unclear. We evaluated the anticonvulsant effects of VPA on CA3 under conditions of [quot]high burst probability.[quot] We measured changes in the interburst interval, burst duration, and thresholds for burst initiation and termination, before and after blockade of GABA[sub]A[/sub] receptors.
In adult rats, 400 micron slices were prepared using a modified ACSF with high sucrose/glucose (75/25mM), high Mg²⁺ (7mM) and low Ca²⁺ (0.5mM). We used extracellular field recordings to examine spontaneous bursting induced under conditions of [quot]high burst probability[quot] ([K⁺][sub]o [/sub]8.5mM) with and without addition of 100[mu]M picrotoxin to block GABA[sub]A[/sub] synaptic transmission. Anticonvulsant effects of VPA (200[mu]M, 1mM, 5mM) on CA3 were evaluated.
Our preliminary data show that in [quot]high burst probability[quot] when GABA[sub]A[/sub] activity was blocked, addition of VPA (200[mu]M to 5mM) did not significantly alter the interburst interval and burst duration. Similarly, in [quot]high burst probability[quot], when GABA[sub]A [/sub]activity was intact, application of 200[mu]M and 1mM VPA did not significantly alter interburst interval or burst duration. However, 5mM VPA increased the interburst interval from control by 306% and decreased the burst duration by 15%. This corresponds to an increase in the burst start threshold of 44% and increase in the burst end threshold of 42%.
1. These observations suggest that the anticonvulsant effects of VPA are mediated via the GABAergic inhibitory system. 2. We plan future studies to examine VPA effects in [quot]low burst probability[quot] (3.3mM K⁺) with and without blockade of the GABAergic system.
[Supported by: NIH]