Neuronal circuitry of thalamocortical epilepsy and mechanisms of antiabsence drug action.

Powerful mechanisms exist within the thalamus that lead to the promotion of synchronous and phasic 3 Hz neuronal activity. These mechanisms include robust burst-firing capability of thalamic neurons, recurrent excitatory and inhibitory synaptic connectivity, and long-lasting and powerful inhibitory synaptic responses arising from activity in thalamic reticular neurons and mediated by gamma-aminobutyric acid (GABA) receptors. The 3 Hz thalamic synchronization appears to arise from a perturbation of a physiologic, higher frequency spindle oscillation. Two currently available antiabsence medications interact with this circuitry with the net result of decreased synchronization, largely through reduction in inhibitory output from the thalamic reticular nucleus. Ethosuximide blocks T-type calcium channels and thus reduces the ability of thalamic neurons to fire bursts of spikes, thereby reducing inhibitory (and excitatory) output within the circuit. By contrast, clonazepam enhances recurrent inhibitory strength within the reticular nucleus. This results in a decreased ability of neighboring inhibitory neurons to fire synchronously and produce the powerful inhibitory synaptic responses that are required for network synchronization.