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 in CA3. We have described convulsant and anticonvulsant effects on spontaneous CA3 population bursts (Yee et al, JNP, 2003). Now, we attempt to validate this model by examining effects of anticonvulsants used in clinical practice on the CA3 system.
Valproic Acid (VPA) is used to treat status epilepticus and generalized and partial epilepsy. However, the underlying mechanisms of VPA remain unclear. We examined the effects of VPA on CA3 when burst probability was low by measuring changes in the interburst interval, burst duration, and thresholds for burst initiation and termination with and without the inhibitory GABA[sub]A[/sub] system intact. In adult rats, 400 micron slices were prepared in artificial cerebral spinal fluid in standard fashion. We used extracellular field recordings to examine spontaneous bursting induced under conditions of [ldquo]low burst probability[rdquo] in modified ACSF ([K⁺][sub]o[/sub] 3.3mM, [Mg2⁺][sub]o [/sub]0.9mM, [Ca2⁺][sub]o [/sub]1.3mM) with and without addition of 100uM picrotoxin (PTX). Effects of VPA 5mM were evaluated. 1. When the inhibitory system was intact, 5mM VPA increased the interburst interval by 300% and decreased burst duration by 23% (n=6).
2. When the inhibitory system was blocked by 100uM PTX, 5mM VPA increased the interburst interval by 154% and decreased the burst duration by 13% (n=4).
3. When we examined changes in the burst start and burst end thresholds, addition of VPA 5mM did not significantly change the [italic]difference[/italic] between the bursting thresholds [control 0.27; 5mM VPA 0.25; (n=6; ttest = 0.48)].
4. Similarly, when the inhibitory system was [italic]blocked[/italic] with 100uM PTX, the difference between the bursting thresholds also did not significantly change in control conditions vs 5mM VPA [control 0.37; 5mM VPA 0.33; (n=6; ttest =0.54)] . 1. The changes in the interburst interval and burst duration suggest that an intact inhibitory system augments VPA effects on CA3 spontaneous bursts.
2. However, the lack of significant changes in the bursting thresholds suggests that the effects of VPA are independent of the inhibitory systems in CA3.
3. We are in the process of performing additional experiments to reconcile these seemingly disparate findings on the effects of VPA on CA3 spontaneous bursts. (Supported by AES, NIH)