Abstracts

Experimental and clinical studies have demonstrated the ability to shorten or terminate epileptiform discharges by application of external electrical stimulation. However, there is no accepted explanation of the mechanism of this action. Recent experimental data illustrate the importance of the short-term frequency dependent plasticity of synapses in the epileptic brain. We used computer simulations of a large neural network model to investigate how a network with short-term synaptic plasticity responds to external stimulation with different frequency parameters. Our model consists of an array of up to 1,000,000 synaptically connected excitatory and inhibitory neuronsNeurons are modeled using a conductance-based model producing realistic action potentials and bursts of action potentials. The synaptic connections are modeled using a double exponential conductance function producing realistic postsynaptic potentials. The strength of connections is modeled by a multiplicative synaptic weight parameter. In our previous publications we have shown that such a model can support the propagation of epileptiform activity. We have also shown that the balance between excitatory and inhibitory synaptic weights is a crucial parameter of network excitability. In this study we simulated short-term synaptic plasticity by introducing activity-dependent synaptic weights to the model. We used a model in which excitatory and inhibitory synapses have the same short-term plasticity characteristics, as well as a model in which these characteristics were different. The initial parameters of the network were set to produce the epileptiform bursting activity. External stimulation was applied to the network immediately or after a delay. The frequency and duration of the applied stimulus were varied between 0.1 Hz and 200 Hz, and between 10 ms and 200 ms, respectively. Addition of activity-dependent synaptic plasticity enhanced the observed dynamics of simulated epileptiform activity. Synchronization of this activity was dependent on the characteristics of synaptic plasticity. If there was stronger potentiation for inhibitory synapses than for excitatory synapses, the seizure terminated spontaneously. External stimulation with relatively high frequencies ([gt]50Hz) terminated these seizures more quickly. When synaptic weights were modeled as depressed for stimulus trains delivered at lower frequencies and potentiated for higher frequencies, a low frequency stimulation was more effective in terminating epileptiform activity. Short-term activity-dependent synaptic plasticity is a plausible mechanism explaining the effects of electrical stimulation on epileptiform activity. The effectiveness of a stimulus at a particular frequency is dependent on synaptic plasticity characteristics. This suggests that different stimulus frequencies may be effective in different brain structures. (Supported by NIH grant NS38958.)