Abstracts

Rationale: T-type calcium channels dysfunction has been implicated in animal models of absence epilepsy. Isolation of human T-type calcium channel genes has allowed the effects of both medications and channel mutations to be studied in vitro (Gomora, 2001). However, it is difficult to predict how changes in channel electrophysiology will affect the behavior of the network as a whole. Here, we use a computer thalamocortical model of 3Hz spike and wave seizure (Destexhe, 1998) to compare the effects of changes in channel conductance, shift in steady state activation / inactivation curves, and inactivation time constant in reticular nucleus T-type calcium channels.Methods: The computational model was comprised of 4 rows of 100 neurons, corresponding to pyramidal and inhibitory neurons in the cortex and relay and reticular nucleus neurons in the thalamus, each based on Hodgkin-Huxley formalism and derived from voltage-clamp data of intrinsic and synaptic currents of animal neurons. The simulated network was allowed to come to steady state, then weak or strong stimuli were given either to thalamic relay cells or pyramidal cells and the duration and organization of spike and wave activity discharges was observed. Reticular nucleus T-type calcium channel parameters for conductance, steady state activation/inactivation voltage shift, and inactivation time constant were serially modified to find bifurcation points for each.Results: Results for each simulation were visualized using 2 dimensional maps of voltage versus time and neuron for each layer (figure 1). Ranges for parameters of reticular nucleus T-type calcium channels supporting sustained spike and wave discharges are listed in table 1. Within these ranges, spike and wave discharges continue for two seconds, when they are stopped by increasing Ih in thalamic relay cells. Outside of these ranges, discharges either failed to be elicited due to lack of bursting in reticular nucleus neurons, or quickly became disorganized. Spike and wave discharges were sustained over a larger range of conductance and shift for strong stimuli as compared to weak stimuli; in contrast, the range of inactivation time constant values that supported spike and wave discharges was largely independent of stimulus size.Conclusions: These results provide useful guidelines for interpreting the clinical implications of reticular nucleus calcium channel electrophysiology. Given that the range of conductance supporting spike and wave discharges depends on the stimulus size, conductance likely plays a more important role in preventing the initiation of spike and wave discharges, while decreasing the inactivation time constant primarily inhibits propagation of spike and wave discharges through the thalamocortical network.