Mechanisms underlying the development of cellular hyperexcitability in mouse models of human epilepsy

Coordinator:    Prof. Dr. Heinz Beck
Institution: Klinik für Epileptologie, Bonn
Changes in voltage-gated ion channels or directly associated proteins are key mechanisms of both genetic and acquired forms of epilepsy. Intriguingly, there is significant overlap between genetic and acquire epilepsies with respect to the affected channel types. In both classes of epileptic disorders, the mechanisms that lead from sometimes subtle changes in the function of a specific ion channel to chronically increased neuronal excitability and epilepsy are not well understood. We propose to use high-resolution cellular physiology and molecular biology to study the mechanisms leading from a single gene mutation to hyperexcitability in a number of novel mouse models.
We will address the following three key questions:

- How do ion channels associate with genetic and/or acquired epilepsies shape intrinsic properties of both principal cells and inhibitory interneurons? How do changes in these neuron types collectively affect behavior of the neuronal ensemble?

- How do epilepsy-associated mutations in these ion channels affect cellular function of native neurons, and behavior of the neuronal ensemble?

- Which adaptive changes take place in principal neurons following
i) complete loss of a particular ion channel subunit protein,
ii) genetic/pharmacological inactivation of the channel function or
iii) introduction of specific epilepsy-associated mutations in ion channel subunits.

These studies will begin to address the complexity of functional and adaptive changes in different neuronal cell types. We expect them to lead to a deeper understanding of the effects of genetic or acquired changes in ion channels on a cellular and network level. llu
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