Cellular Actions of Petit Mal Anticonvulsants: Implication of Thalamic Low-Threshold Calcium Current in Generation of Spike-Wave Discharge

Abstract

Typical absence or petit mal seizures are associated with large amplitude, synchronized, low-frequency spike-wave discharges (SWD) on the electroencephalogram. Extracellular recordings both thalamic and cortical neuronal activity during SWDs in animal models of petit mal (Gloor and Fariello, 1988; Vergnes, et al., 1987) and EEG and depth recordings in the thalamus and cortex of humans during petit mal attacks (Williams, 1953) have demonstrated that these 3/second rhythms are due to an underlying thalamocortical oscillatory interaction. Other types of thalamocortical oscillatory behavior, such as sleep spindles, involve a complex interaction between synaptic excitatory and inhibitory connections and intrinsic membrane conductances in both thalamic and cortical areas (Steriade and Deschênes, 1984; Steriade and Llinás, 1988). Similar rhythmic activity can be recorded in the isolated thalamus (Morison and Bassett, 1945). A low-threshold calcium conductance, particularly prominent in thalamic neurons, has been shown to be of primary importance in the generation of oscillatory behavior in the thalamus (Jahnsen and Llinás, 1984a,b; Deschênes et al., 1982), including that which occurs during sleep spindles (Steriade and Deschênes, 1984; Steriade and Llinás, 1988). It has been hypothesized for decades that the thalamocortical mechanisms involved in the generation of recruiting responses and spindle rhythms are also involved in the generation of SWD (Jasper and Droogleever-Fortuyn, 1946). In addition, there is a significant correlation between the occurrence of sleep spindles and SWD in petit mal epileptics (Kella-way, 1985), as well as during the induction of SWD in a feline penicillin model of generalized SWD (Gloor and Fariello, 1988), which suggests a potential similarity in the underlying mechanisms. We therefore hypothesized that the low-threshold calcium conductance in thalamic neurons might be important in the generation of SWD and petit mal attacks. One of the most selective drugs for the control of petit mal epilepsy is ethosuximide (Brown et al., 1975). However, no cellular mechanism of action for this agent, consistent with its clinical utility, has been demonstrated. We reasoned that one mechanism by which ethosuximide might control SWD would be to reduce the calcium conductance underlying low-threshold calcium spikes in thalamic neurons, thereby dampening the thalamocortical oscillation underlying (and generating) petit mal attacks. To investigate potential cellular mechanisms of action of ethosuximide, and to provide further support for our hypothesis concerning the importance of low-threshold calcium spikes in the generation of SWD, we examined the effects of ethosuximide on current- and voltage-clamped thalamic neurons in vitro. Our findings suggest that the low-threshold calcium conductance in thalamic neurons is an important cellular event in the generation of SWD. In addition to demonstrating a cellular mechanism for the action of ethosuximide and other specific petit mal anticonvulsants, our data also provide a new testable hypothesis concerning potential crucial factors in the pathogenesis of petit mal epilepsy.KeywordsCalcium CurrentPotassium CurrentSleep SpindleThalamic NeuronRepeatable MannerThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.