Abstracts

RATIONALE: Spontaneous mutation of the Ca2+ channel ?-2 subunit results in a mouse model, stargazer (stg), with an absence epilepsy phenotype similar to that in humans. However, how the mutation of this Ca2+ channel subunit leads to spike and wave discharges is still unknown. The properties of voltage-dependent Ca2+ channel currents in thalamic neurons are crucial in generating thalamocortical rhythmicity and regulating membrane excitability, and may play a key role in abnormal synchronization associated with absence epilepsy. We hypothesized that Ca2+ currents are altered in thalamocortical relay cells (TCs) in stg mutants. METHODS: We examined the electrophysiological properties of both low-voltage activated (LVA) and high-voltage activated (HVA) Ca2+ currents in TCs of the lateral dorsal nucleus (LDN) using whole-cell patch clamping of coronal brain slices of 2~3 week-old stg and control (C57BL/6J) mice. RESULTS: We observed a 50% increase in peak current density of LVA Ca2+ currents evoked at -50 mV from -110 mV in stg relative to control. In addition, the midpoint voltage (V1/2) for steady-state inactivation of LVA currents in stg (-76.86?2.2 mV) shifted to a depolarized direction for ~12 mV compared to control (-89.61?4.0 mV). For HVA Ca2+ currents, there was a 40% increase in peak current density in stg relative to control. The voltage dependence of steady-state activation for HVA currents was similar between control and stg. CONCLUSIONS: Our data indicate that a depolarized shift in the voltage dependence of steady-state inactivation may contribute to increased LVA Ca2+ currents in LDN TCs in stargazer mice. These data also suggest that the ?-2 subunit is a component of both LVA and HVA Ca2+ channels in vivo. This is the first direct evidence that a Ca2+ channel mutation increases low-voltage activated Ca2+ channel currents in thalamocortical relay cells and produces spike-wave seizures. Supported by NS29709 (JLN).