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

Abstract

Actions of U-92032, a T-type Ca 2ϩ channel antagonist, support a functional linkage between I T and slow intrathalamic rhythms. J Neurophysiol 89: 177-185, 2003; 10.1152/jn.00667.2002. Thalamic relay neurons express high levels of T-type Ca 2ϩ 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 Ca 2ϩ -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. Ca 2ϩ -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 M) 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 M) 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 (Յ2 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 Tchannel antagonists may provide effective drug treatments for absence epilepsy.

Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

“…Pharmacological studies suggest that low-voltage-activated T-type Ca 2ϩ channels are involved in the genesis of absence seizures, which are characterized by spike-and-wave discharges (SWDs) (van Luijtelaar et al, 2000;Porcello et al, 2003). Antagonists of T-type Ca 2ϩ channels suppress both slow intrathalamic rhythms in vitro (Porcello et al, 2003) and SWDs in human absence seizure patients and in rodent models of absence seizures (Heller et al, 1983;Hosford et al, 1992;van Luijtelaar et al, 2000).…”

“…Antagonists of T-type Ca 2ϩ channels suppress both slow intrathalamic rhythms in vitro (Porcello et al, 2003) and SWDs in human absence seizure patients and in rodent models of absence seizures (Heller et al, 1983;Hosford et al, 1992;van Luijtelaar et al, 2000). Previous genetic studies indicate that of the three ␣1 subunits of T-type Ca 2ϩ channels (G, H, and I), the ␣1G subunit is critically involved in SWD genesis.…”

Targeted Resequencing of Epilepsy Genes: A Pharmaco-Therapeutic Perspective

“…Hence, LVA calcium T-channels are considered essential players in the regulation of neural pacemaker activity and synchronized neuronal oscillations of thalamocortical networks and responsible of spike wave discharge in absence epilepsy [79,80]. Indeed, variants in the CACNA1H gene are considered risk factors for susceptibility to IGEs pathogenesis [81] and different single nucleotide polymorphisms of this gene have been found associated to CAE [82].…”

Drugs Active at T‐type Ca 2+ Channels

“…One well-studied example is the flunarizine analog U-92032 [69] which is three-orders of magnitude more potent at T-Type channels than methylphenylsuccinimide (MPS) [70].…”