Investigators' Workshop Poster Session 4:30 p.m.-6:00 p.m.

Abstract

Abstract Pawel Kudela 1 , W. S. Anderson 2 , P. J. Franaszczuk 1 and G. K. Bergey 1 ( 1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD and 2 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD ) Rationale: Dysfunctions of voltage activated calcium channels (VACCs) have been reported in the hippocampal neurons derived from human temporal lobe epilepsy patients and appropriate animal models. They include up- or down-regulation and/or alterations in density and distribution of a variety of Ca2+ channels. Although it is accepted that these dysfunctions are implicated in epileptogenesis, the actual role of particular Ca2+ currents is not clearly understood. In these computational studies we analyze the effect of modifications of various VACCs on the regulation of Ca2+ entry and neuronal excitability. Methods: Ca2+ dynamics is modeled in a spherical neuron model which incorporate several concentric shells and takes into account calcium influx and extrusion through the plasma membrane and binding to two buffer systems. The total calcium current was separated amongst the three groups of currents: Cav1 (L-type), Cav2 (P,N, and R-type), and Cav3 (T-type). Two forms of L-type calcium currents were included in the model: Cav1.2 high threshold activated at 4 mV and Cav1.3 low threshold activated at −45 mV. Kinetics for Ca2+ currents were taken from the most recent available data for these currents. The 1.3 L-type channel is only partly characterized so the Ca2+-dependent inactivation of Cav1.3 was assumed. The up- or down-regulation of L-type channels was simulated by changing the ratio of Cav1.2 to Cav1.3. Results:[Ca2+]i in neurons rises abruptly after suppression of inhibitory drive in the network and the rate of the [Ca2+]i rise is an order of magnitude higher compared to the rate of rise in a network with active inhibition. [Ca2+]i levels increase from the initial 0.05 μM and show a plateau effect approximately at 0.6 μM in disinhibited networks and 0.15 μM in a network with active inhibition. Simulation of prolonged neuronal depolarization revealed that activation of the Cav1.3 L-type current helps depolarize neuronal membrane to a threshold value. In elevated [Ca2+]i conditions, when Ca2+-dependent inactivation of Cav1.3 is modeled, neurons exhibit recurrent neuronal bursting resulting from cyclic activation and inactivation of Cav1.3 L-type current. This observation has been confirmed in network models where reversing the ratio of Cav1.2 to Cav1.3 resulted in switching of neurons behaviors from continuous firing to recurrent bursting. Conclusions: The results of simulations indicate that [Ca2+]i and VACCs might be implicated in the regulation of membrane excitability, and after the withdrawal of inhibition promote the conditions leading to recurrent neuronal bursting. Our results suggest that up-regulation of low threshold VACCs notably increases the rate of Ca2+ transport through the plasma membrane. [Ca2+]i in neurons rises to significantly higher levels in disinhibited networks compared to neurons in networks with active inhibition. Enhanced expression of low threshold VACCs, particularly Cav1.3 L-type, can contribute to recurrent neuronal bursting and these channels represent potentially interesting therapeutic targets for antiepileptic drugs. Supported by NIH NS51382,NS38958, and Epilepsy Foundation