Abstracts

It has been suggested that Ca²⁺ entry through Ca²⁺ dependent K⁺ channels activates K⁺ channels, i.e., slow Ca²⁺- activated K⁺ channels (sI[sub]AHP[/sub]), that help terminate epileptiform activity. Although the importance of the sI[sub]AHP[/sub] channels for the termination of epileptiform activity has been studied, it is not clear which parameters in the sI[sub]AHP[/sub] kinetics are important. The present study investigates how changing parameters in the sI[sub]AHP [/sub]kinetics influences network behavior, particularly whether changes in parameters of the sI[sub]AHP [/sub]kinetics can terminate synchronized bursting activity of the network.
A multicompartmental pyramidal model of synaptically connected neurons was constructed using the simulation software GENESIS. Three simplified pyramidal neurons and an interneuron were modeled in this study: two neurons synaptically connected with excitatory synapses form a loop, a neuron where random input is applied to generate action potentials, and an inhibitory interneuron, which synapses on one of the modeled pyramidal neurons, in a negative feedback loop. The soma of the pyramidal neuron and inhibitory interneuron has a fast sodium (I[sub]Na[/sub]), delayed potassium (I[sub]KDR[/sub]), transient potassium (I[sub]A[/sub]), high-threshold calcium (I[sub]Ca[/sub]), and sI[sub]AHP[/sub] channels, and short-duration voltage and calcium dependent potassium channels (I[sub]KC[/sub]). The influences of changes in parameters of the sI[sub]AHP [/sub]kinetics, i.e., maximum conductance, forward or backward rate functions, and resting membrane potential, on terminating bursting activity were investigated.
Simulations show that the maximum conductance and forward rate function in the sI[sub]AHP [/sub]kinetics regulate the patterns of bursting activity. When the sI[sub]AHP [/sub]activity is decreased by reducing the maximum conductance of the sI[sub]AHP [/sub]for both the pyramidal neuron and inhibitory interneuron, bursting activity is terminated in this neuronal circuit model. Bursting activity is also terminated if a parameter in the forward rate function of the sI[sub]AHP [/sub]for both the pyramidal neuron and inhibitory interneuron is decreased. However, there are no changes when the resting membrane potential or backward rate constant of the sI[sub]AHP[/sub] for both the pyramidal neuron and inhibitory interneuron is decreased or increased.
Changes in the kinetics of the sI[sub]AHP[/sub] can influence bursting behavior in a neuronal circuit model of pyramidal cells. The maximum conductance and forward rate function of the sI[sub]AHP[/sub] kinetics were found to regulate bursting activity. Decreased sI[sub]AHP [/sub]activity by reducing maximum conductance, or decreasing the parameter of the forward rate function in the sI[sub]AHP [/sub]kinetics terminates bursting activity. It is the presence of the inhibitory interneuron that results in decreased bursting of the network when the activity of the sI[sub]AHP[/sub] is reduced. Without the inhibitory interneuron, bursting activity would increase. This study has implications for how the dynamics of the sI[sub]AHP[/sub] can influence network excitability during epileptiform discharges.
[Supported by: NIH grant NS 38958.]