The Journal of Neurophysiology Vol. 87 No. 1 January 2002, pp. 62-71
Copyright ©2002 by the American Physiological Society

Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices

 ¹Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106; and  ²Department of Neurological Surgery, University of California, San Francisco, California 94143

Bikson, Marom, Scott C. Baraban, and Dominique M. Durand. Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices. J. Neurophysiol. 87: 62-71, 2002. Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca²⁺ concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca²⁺ levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca²⁺ reduction in normal Ca²⁺ levels. Increasing neuronal excitability, by removing extracellular Mg²⁺ and increasing extracellular K⁺ (6-15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [D-()-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of K_Ca antagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba²⁺) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg²⁺ and increasing extracellular K⁺) in the presence of Cd²⁺, a nonselective Ca²⁺ channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca²⁺ facilitates bursting by increasing neuronal excitability and inhibiting Ca²⁺ influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca²⁺ levels.