Abstracts

RATIONALE: Ca²⁺ currents within the thalamocortical circuit play a critical role in membrane excitability and the generation of synchronous burst firing in absence epilepsy. Our previous data demonstrated an increase in thalamic Ca²⁺ currents in [italic]stargazer[/italic] ([italic]stg[/italic]) mice with a mutation of the Ca²⁺ channel [gamma]2 subunit. In this study, we hypothesized that Ca²⁺ channel currents are also altered in thalamocortical relay cells (TCs) in the mouse absence models with mutations in the Ca²⁺ channel [alpha]1A subunit, [italic]tottering([/italic]tg), and [beta]4 subunit, [italic]lethargic[/italic]([italic]lh[/italic]).
METHODS: We compared the biophysical properties of both low-voltage activated (LVA) and high-voltage activated (HVA) Ca²⁺ currents in TCs of the lateral dorsal nucleus (LDN) using the whole-cell patch clamp technique in coronal brain slices of the two mutants and control (C57BL/6J) mice.
RESULTS: We observed 46% and 52% increases in peak current densities of LVA Ca²⁺ currents evoked by a test pulse to -50 mV from a prepulse at -110 mV in [italic]tg[/italic] and [italic]lh[/italic] mice respectively, relative to control values. The midpoint voltage (V[sub]1/2[/sub]) for steady-state inactivation was shifted in a depolarized direction by 7.5 mV in [italic]tg[/italic] and 13.5 mV in [italic]lh[/italic] compared to the value in control. The time-constants for recovery from inactivation of LVA currents in wild type, [italic]tg[/italic], and lh were 409, 411, and 331 ms respectively. For HVA Ca²⁺ currents, there were no significant changes in peak current densities in both [italic]tg[/italic] and [italic]lh[/italic] mutants compared to control.
CONCLUSIONS: Our data suggest that the increased thalamic LVA peak currents and depolarized shift of the voltage dependence of inactivation may contribute to membrane hyperexcitability and increase the probability for neuronal synchronization. Recent data raise the possibility that the [gamma]2 subunit mutation in [italic]stargazer[/italic] may not regulate neuronal voltage-gated Ca²⁺ channels. Our results indicate that altered Ca²⁺ currents in thalamic neurons are associated with the spike-wave epilepsy phenotype in mutations of known Ca²⁺ channel subunits.
Support: NS29709 (JLN).