HIPPOCAMPAL NEURON EXCITABILITY FOLLOWING SIEZURES

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

Chronic models of epilepsy such as pilocarpine-treated rodents have proven useful for studies of the molecular and cellular events that are responsible for the conversion of a brain from normal to epileptic. This proposal focuses initially on elucidating the basis for a form of disinhibition in the pilocarpine model, then extends key observations to other chronic models. The firing rate of dentate granule cells is controlled by a variety of interneurons as well as a high spike threshold. Our major working hypotheses that will be explored in the next project period is that GABAergic inhibition in the epileptic state appears normal at low firing rates, but during high frequency firing, inhibition fails selectively due to failure of excitatory transmission onto the interneurons. Our preliminary data support this hypothesis. This form of short-term depression (STD), a selective loss of excitatory drive to dentate interneurons during repetitive (but not low frequency) activation, is well-suited to contribute to long- term dysfunction of hippocampal networks following repeated seizures. The specific aims are i) To identify pre- and postsynaptic receptors that regulate the strength of STD of excitatory drive onto dentate hilar border interneurons; ii) To determine whether depletion of a readily releasable pool of transmitter contributes to STD during brief spike trains; iii) To determine the basis for enhanced STD in the pilocarpine model; iv) To evaluate the role of enhanced STD in epileptogenesis. Our goal is to understand the role of short-term plasticity on the global response of the dentate-CA3 network to repetitive inputs in the epileptic state. These experiments should provide new information on the regulation of short- term synaptic plasticity of excitatory inputs to interneurons and pyramidal cells in normal and epileptic hippocampus. The experiments proposed are relevant to achieving a better understanding of hippocampal circuitry involved epilepsy, memory, and information processing through the hippocampus.