The Influence of Slow Calcium-Activated Potassium Channels on Epileptiform Activity in a Neuronal Model of Pyramidal Cells

An imbalance between excitation and inhibition can play an important role in the generation of epileptiform activity. Experimental evidence indicates that alterations of either synaptic activity or intrinsic membrane properties may contribute to this imbalance. The slow Ca activated K currents (sIAHP) limit neuronal firing rate and excitability and are therefore of great interest for their potential role in epileptogenesis. The sIAHP is found in both excitatory and inhibitory neurons, and its effect on these neurons can influence the network behavior. Simulations show that the increased excitability caused by reduction of inhibition by the sIAHP for inhibitory interneuron generates recurrent bursting activity. Background and Significance Neuronal hyperexcitability and epileptiform activity are associated with an imbalance between excitatory and inhibitory synaptic activity and/or alterations of neuronal intrinsic properties (Bernard et al., 2000; During et al., 1995; Olsen and Avoli, 1997; Treiman, 2001). GABAergic inhibition controls neuronal excitability in such a way that a change in GABAergic inhibition is thought to be important for many forms of human or experimental epilepsy (Bernard et al., 2000; Freund and Buzsáki, 1996; Prince, 1978; Treiman, 2001). There is evidence from in vitro experiments that reduced GABAergic inhibitory synaptic activity (Federico and MacVicar, 1996; McBain, 1994; Rodriguez-Moreno et al., 1997; Wong and Miles, 1994) or increased glutamatergic excitatory synaptic activity (Federicon and MacVicar, 1996; Johnston and Brown, 1981; Traub et al., 1993) leads to epileptiform activity. The array of potassium channels expressed by a neuron is a major factor in determining its excitability. Studies of human epileptic hippocampus indicate that changes in the properties of some potassium channels may contribute to neuronal hyperexcitability and epileptogenesis (Beck et al., 1996; Biervert et al., 1998). The slow Caactivated K current (sIAHP) mediates the postspike after hyperpolarization (AHP) that limits excitability of pyramidal neurons (Alger and Nicoll, 1980; Behr et al., 2000; Empson and Jefferys, 2001; Verma-Ajuja et al., 1995). Alger and Nicoll (1980) suggested that the Cadependent K current is important in preventing the development of seizure-like activity. In addition, Empson and Jefferys (2001) suggested that Ca entry through L-type Ca channels activates a K current that helps terminate epileptiform activity. While the studies summarized above suggest that sIAHP controls the excitatory output of neuronal networks by altering intrinsic neuronal excitability, an unknown factor in these experiments is the role of interneurons. Interneurons also control the excitatory output of networks by providing feedback inhibition onto excitatory neurons. Interneurons, like pyramidal neurons, possess sIAHP (Zhang and McBain, 1995; McQuiston and Madison, 1999). In contrast to pyramidal neurons, reducing sIAHP and thereby increasing excitability in inhibitory interneurons would be expected to reduce rather than enhance the overall excitability of the network. When this added complexity is considered, it becomes less clear how various modulators may affect network behavior. Experiments employing simultaneous intracellular recordings of pyramidal neurons and interneurons to determine how changes in sIAHP may correlate with epileptogenesis would require a universally accepted model of epilepsy and the capability to perform complex data analysis. This type of experiment may be modeled using a small network of pyramidal cells and an interconnected inhibitory interneuron. Using the computational approach will allow the simultaneous monitoring of individual neurons’ membrane behavior as well as the behavior of the entire network. In addition, the individual conductance on each cell membrane can be modified and the resulting effect on network behavior tested. In this way, a carefully controlled study of the role of sIAHP and its modulation in epileptogenesis can be performed. The results of this study may guide the design of biological experiments to verify where alterations or abnormal regulation of these important channels may occur in epilepsy, and may suggest key targets for therapeutic