Epilepsy: A Window to Brain Mechanisms

In our lab we study basic cellular mechanisms of neuronal function in mammalian cortical structures. Our main focus is on mechanisms that underlie epilepsy, a common neurological disorder (0.5-1% world-wide), characterized by recurrent seizures. A seizure is a sudden interruption in normal brain function during which a large population of neurons fires repetitively and in high synchrony. A cortical structure having a low threshold for seizure generation is the hippocampus. Even when cut into thin slices and maintained in a dish in artificial physiological conditions, rat hippocampal tissue readily can be induced to generate seizure-like discharges. This provides us with an experimentally advantageous model for studying the cellular and molecular mechanisms of epilepsy.

 

Using electrophysiological techniques, we monitor the activity of single hippocampal neurons in slices for several hours. The changes occurring in these cells as they are recruited into seizure discharge are recorded and analyzed. We have recently found that a common feature of acute models of epilepsy is the presence of a subclass of hippocampal neurons which have a high propensity to generate bursts of action potentials. These intrinsic bursters are recruited before all other neurons during the initiation of an epileptic event and, therefore, must be the initiators of these events. Moreover, in a widely used model of chronic epilepsy, the pilocarpine model, we found that most hippocampal neurons change from regular firing to burst firing behavior. We are currently investigating the molecular and cellular mechanisms underlying the induction and expression of intrinsic bursting in hippocampal neurons in both acute and chronic epileptic tissue. It so far appears that the development of the epileptic condition (i.e. epileptogenesis) is associated with both transcriptional and posttranscriptional upregulation of certain calcium and sodium voltage-gated channels. We also investigate the synaptic and electric mechanisms by which this activity in single neurons recruits and synchronizes the entire neuronal network during epileptiform discharges.