The Journal of Neurophysiology Vol. 82 No. 2 August 1999, pp. 946-954
Copyright ©1999 by the American Physiological Society

Ca²⁺-Dependent Inactivation of High-Threshold Ca²⁺ Currents in Hippocampal Granule Cells of Patients With Chronic Temporal Lobe Epilepsy

 ¹Department of Epileptology, University of Bonn Medical Center, D-53105 Bonn; and  ²Department of Neurophysiology, Institute of Physiology, Charité Berlin, D-10117 Berlin, Germany

Beck, Heinz, Ralf Steffens, Uwe Heinemann, and Christian E. Elger. Ca²⁺-Dependent Inactivation of High-Threshold Ca²⁺ Currents in Hippocampal Granule Cells of Patients With Chronic Temporal Lobe Epilepsy. J. Neurophysiol. 82: 946-954, 1999. Intracellular Ca²⁺ represents an important trigger for various second-messenger mediated effects. Therefore a stringent control of the intracellular Ca²⁺ concentration is necessary to avoid excessive activation of Ca²⁺-dependent processes. Ca²⁺-dependent inactivation of voltage-dependent calcium currents (VCCs) represents an important negative feedback mechanism to limit the influx of Ca²⁺ that has been shown to be altered in the kindling model of epilepsy. We therefore investigated the Ca²⁺-dependent inactivation of high-threshold VCCs in dentate granule cells (DGCs) isolated from the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE) using the patch-clamp method. Ca²⁺ currents showed pronounced time-dependent inactivation when no extrinsic Ca²⁺ buffer was present in the patch pipette. In addition, in double-pulse experiments, Ca²⁺ entry during conditioning prepulses caused a reduction of VCC amplitudes elicited during a subsequent test pulse. Recovery from Ca²⁺-dependent inactivation was slow and only complete after 1 s. Ca²⁺-dependent inactivation could be blocked either by using Ba²⁺ as a charge carrier or by including bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) or EGTA in the intracellular solution. The influence of the cytoskeleton on Ca²⁺-dependent inactivation was investigated with agents that stabilize and destabilize microfilaments or microtubules, respectively. From these experiments, we conclude that Ca²⁺-dependent inactivation in human DGCs involves Ca²⁺-dependent destabilization of both microfilaments and microtubules. In addition, the microtubule-dependent pathway is modulated by the intracellular concentration of GTP, with lower concentrations of guanosine triphosphate (GTP) causing increased Ca²⁺-dependent inactivation. Under low-GTP conditions, the amount of Ca²⁺-dependent inactivation was similar to that observed in the kindling model. In summary, Ca²⁺-dependent inactivation was present in patients with TLE and Ammon's horn sclerosis (AHS) and is mediated by the cytoskeleton similar to rat pyramidal neurons. The similarity to the kindling model of epilepsy may suggest the possibility of altered Ca²⁺-dependent inactivation in patients with AHS.