Theoden NETOFF

Biomedical Engineering, University of Minnesota, Minneapolis

How do antiepileptic drugs and epileptogenic mutations change cell and network dynamics?

Epilepsy is characterized by periods of excessive neuronal activity called seizures. While much is known about population behaviors of neurons during seizures, as measured by EEG electrodes, very little is known about the activity at the cellular level. The etiology of the disease can often be traced to specific mutations in particular ion channels. These same ion channels are often the targets of antiepileptic drugs. Bridging the molecular scale causes and treatment of epilepsy to the network scale phenotype is a multi-scale problem that needs to be solved in order to develop more rational approaches to treating epilepsy.

Our research seeks to understand the basic mechanisms of epilepsy by understanding how network synchrony is affected by molecular level changes caused by epileptogenic mutations and antiepileptic drugs. Our approach is guided by experimental evidence, in a rat model of epilepsy, indicating that synchrony in the network changes over the different phases of the seizure. Synchrony among neurons is relatively high between seizures, drops during the peak of a seizure and then is strongly synchronous towards the end of a seizure. These changes in synchrony may hold a key to understanding what makes some people prone to seizures and how to treat epilepsy. However, why synchrony changes during a seizure is still a mystery.

To better understand how neurons synchronize, we use pulse coupled oscillator theory. We reduce the dynamics of the neuron to a simple input-output relationship by measuring how synaptic inputs applied at different phases of a periodically firing neuron advances or delays the spike, resulting in a Phase-Response Curve (PRC). From the measured PRC, it is possible to predict how a network of neurons will synchronize. We then measure how epileptogenic mutations and antiepileptic drugs affect the neuron's PRC to infer how it changes the synchronizability of the network. By measuring the effects of these changes at the molecular level we know causes epilepsy, we can bridge the effect to a population.

This talk will present our computational simulations and in vitro experiments measuring PRCs from neurons. We find that epileptogenic mutations in voltage gated sodium channels and potassium channels affect the neurons' PRCs to increase network synchrony while antiepileptic drugs decrease synchrony. We hypothesize that while many antiepileptic drugs have very different mechanisms of action, their common feature may be that they decrease network synchrony. PRCs can also explain why synchrony changes during the seizure. At very high firing rate, the neurons' PRCs are shifted so that a network of excitatory neurons will actively desynchronize, as we might find at the peak of the seizure. If the firing rate of the neuron slows over the duration of the seizure, the PRC shape changes so that the network will synchronize, resulting in the late synchronous phase of the seizure.