J Neurophysiol (January 1, 2003). 10.1152/jn.00667.2002
Submitted on Submitted 13 August 2002; accepted in final form 3 September 2002.

Actions of U-92032, a T-Type Ca²⁺ Channel Antagonist, Support a Functional Linkage Between I_T and Slow Intrathalamic Rhythms

Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, California 94305

Porcello, Darrell M., Stephen D. Smith, and John R. Huguenard. Actions of U-92032, a T-Type Ca²⁺ Channel Antagonist, Support a Functional Linkage Between I_T and Slow Intrathalamic Rhythms. J. Neurophysiol. 89: 177-185, 2003. Thalamic relay neurons express high levels of T-type Ca²⁺ channels, which support the generation of robust burst discharges. This intrinsically mediated form of phasic spike firing is thought to be critical in the generation of slow (3-4 Hz) synchronous oscillatory activity of absence epilepsy. Recordings made from brain slices or whole animals have shown that slow synchronous absence-like activity can be abolished when Ca²⁺-dependent burst firing in relay neurons is interrupted by the pharmacological or genetic inactivation of T-channels. Because succinimide drugs act as incomplete and nonspecific antagonists, we tested whether the novel T-channel antagonist U-92032 could provide stronger support for a role of T-channels in slow oscillatory activity. Ca²⁺-dependent rebound (LTS) bursts were recorded using whole cell current clamp in relay cells of the ventral basal complex (VB) from thalamic slices of adult rats. We used LTS kinetics to measure the availability of T-channels in VB cells after TTX. U-92032 (1 and 10 µM) reduced the maximum rate of depolarization of the isolated LTS by 51% and 90%, respectively, compared with the 35% reduction due to 2 mM methylphenylsuccinimide (MPS), the active metabolite of the antiabsence drug methsuximide. U-92032 (1 and 10 µM) also suppressed evoked, slow oscillations in thalamic slices with a time course similar for observed intracellular effects. Unlike MPS, we observed no substantial effects of short-term U-92032 applications (2 h) on the generation of action potentials in VB cells. Our findings show U-92032 is a more potent, effective, and specific T-channel antagonist than previously studied succinimide antiabsence drugs and that it dramatically reduces epileptiform synchronous activity. This suggests that U-92032 or other specific T-channel antagonists may provide effective drug treatments for absence epilepsy.