Models of hippocampal neurons

Epilepsy syndromes are a common cause of disability and reduce the quality of life for more than 2 million Americans. In the last decade, physicians and experimentalists have worked in concert to identify inherited mutations that underlie epilepsy. A majority of these mutations have been found in genes encoding specialized ion channel proteins that are highly expressed in the hippocampus. The hippocampus is prone to disruption since the delicate electrical activity necessary for complicated brain rhythms also makes the structure sensitive to small perturbations.  Mutations cause abnormal ion channel behavior, which likely promotes epileptic triggers by disrupting the precision required for normal excitability. The diversity of genes that have been shown to contain epilepsy-linked mutations, suggests that abnormal excitation can stem from distinct, and as yet, elusive mechanisms. One possibility is that runaway excitation can result from both hyperexcitability and hypoexcitability, the mechanisms of which are likely divergent and one of the difficulties in treating epilepsy stems, in part, from the multiple mechanisms and triggers that underlie epileptic events.

The Clancy Lab has begun theoretical investigations of abnormal excitability in the brain, specifically the hippocampus, in order to investigate ionic mechanisms of genetically based epilepsy.  Many of the same modeling methodologies that have been used for revelation of mechanisms of cardiac arrhythmias are now being applied in the lab to study of genetic epilepsy.  We hope that our theoretical investigations will reveal important insights on the molecular basis of abnormal neuronal activity that can trigger epileptic activity. The model predictions are expected to lend insight into the origins of clinical observations, such as the appearance of interictal spike activity on the EEG.  We aim to develop a novel quantitative approach that will enable multiscale investigation of mechanisms of epilepsy, in order to bridge the multiple scales over which epilepsy develops, from genetics to cellular mechanisms, and ultimately to integrated system behaviors.