Regulation of circuit excitability is critical for normal brain function, and a disruption of the delicate balance between excitation and inhibition leads to epilepsy. Exogenous application of kainate (KA) is widely used as an animal model of temporal lobe epilepsy. However, the mechanisms by which KA causes this epileptiform activity are not well understood, and initial studies suggest that functionally distinct subpopulations of KA receptors (KARs) may have conflicting roles in controlling the excitability of the hippocampal circuit. Whether or not KARs are critically involved in the formation of epilepsy in human patients, understanding how the different actions of KARs serve to increase or decrease hippocampal excitability and whether these opposing actions of the receptors are subtype-specific will provide promising insights towards the possible treatment of this disorder. Furthermore, such information will contribute to the general understanding of hippocampal function. Much of the research on KARs has focused on presynaptic regulation of transmitter release, leaving the actions of postsynaptic KARs in synaptic integration poorly understood. The objectives of this proposal are to understand the properties of postsynaptic KAR subtypes and the ways in which they control circuit excitability and synaptic physiology and transmission. These questions will be addressed utilizing whole cell patch clamp electrophysiological techniques in both hippocampal slice and dissociated cell preparations.
The specific aims of this proposal are to compare the functional roles of AMPARs and KARs during synaptic transmission and to identify the mechanisms underlying the KAR-mediated decrease of the afterhyperpolarization, a phenomenon thought to be a putative mechanism for KA lesion-induced hyperexcitability. Epilepsy affects 1-2% of the population, with temporal lobe epilepsy (TIE) as the most common form. The hippocampus, an area of the brain crucial to memory formation, plays a critical role in the generation and spread of seizures, and has been implicated in TLE. Understanding the roles kainate receptors play in cell to cell communication and how they control the excitability of this region of the brain could reveal possible therapeutic targets for treatment of this disorder and a better understanding of epilepsy in general.
| Wondolowski, Joyce; Frerking, Matthew (2009) Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1. J Neurosci 29:563-74 |
