Abstracts

Rationale: The thalamus is a sub-cortical relay structure that produces both physiological spindle-like oscillations (spindles; 10 15 Hz), as well as highly synchronized pathological spike-wave discharges (3 Hz) that, in part, characterize absence epilepsy. This oscillatory activity arises from reciprocal connectivity between inhibitory interneurons of the reticular thalamic nucleus (nRT) and glutamatergic relay neurons of the ventral basal complex (VB). A single period of activity in this circuit is thought to occur when inhibitory nRT neurons induce a GABA-mediated hyperpolarization of relay neurons, thereby deactivating low-threshold T-type calcium channels. Upon repolarization, relay neurons fire a T-type calcium channel-mediated burst of action potentials that re-excites nRT neuron (also in a T-type calcium channel-dependent manner), thus initiating a subsequent phase of the cycle. The lack of selective and specific T-type calcium channel antagonists have, to date, prevented a detailed pharmacological analysis of their role in thalamic oscillatory activity. In this study, we utilize TTA-P2, a novel T-type calcium channel antagonist, to fully characterize the role of T-type calcium channels in an ex vivo slice model of thalamic oscillatory activity.Methods: Horizontal thalamic slices were obtained from P12 P14 Sprague-Dawley rat pups. Slices were placed in an interface chamber and perfused with oxygenated saline at 34 C. Electrical stimuli were delivered to the internal capsule through a pair of 50- to 100-K? bipolar tungsten electrodes. Multiunit extracellular recordings were made with tungsten electrodes placed in VB. Bursting activity corresponds to a population burst composed of many neurons. Apamin (SK antagonist; 1nM) and picrotoxin (GABAAR antagonist; 50 M) were included in bath solution to induce epileptiform-like spike-wave discharges.Results: TTA-P2 (22nM) significantly impaired generation of both spindle-like oscillations and spike-wave discharges, as measured by oscillation duration and burst number. TTA-P2 had a larger effect on spike number (decrease) in the spike-wave condition than in the spindle-like condition. TTA-P2 only affected period (increase) in the spike-wave condition.Conclusions: These data not only confirm the critical role of T-type calcium channels in thalamic oscillatory activity, but also suggest that TTA-P2 may target thalamic epileptiform-like activity more effectively than physiological spindle-like oscillations. We speculate that the enhanced efficacy of TTA-P2 for pathological epileptiform-like oscillations over physiological spindles suggests that pharmacological antagonism of T-type calcium channels represents a viable therapeutic strategy for reducing the aberrant thalamic synchrony characteristic of absence epilepsy while leaving physiological oscillatory activity intact.