Dentate Granule Cell Network in Epilepsy

Nadler, J.

Abstract

This project concerns the role that establishment of recurrent excitatory circuitry in the dentate gyrus plays in temporal lobe epilepsy. Granule cell neurogenesis, aberrant granule cell migration, and mossy fiber sprouting create a reverberating network that can reduce the threshold for granule cell synchronization and potentially diminish the normally high resistance of the dentate gyrus to seizure propagation. Pilocarpine-treated rats, which become epileptic and also develop a consistently dense granule cell network, will be used to investigate the properties and potential pathophysiological role of hilar ectopic granule cells. Many of the new granule cells produced as a result of seizures migrate aberrantly into the dentate hilus. Most hilar ectopic granule cells, unlike other granule cells in either normal or epileptic brain, fire action potentials and/or cellular bursts spontaneously at resting membrane potential. Therefore these cells are hypothesized both to facilitate recruitment of the granule cell population into seizure activity and to enhance excitability in area CA3. Whole cell patch clamp recordings will characterize the innervation of hilar ectopic granule cells and assess the possibility that abundant perisomatic excitation and sparse synaptic inhibition contribute to their unusual excitability. We will also determine to what extent spontaneous firing/bursting can be attributed to enhanced T-type calcium current, expression of h current, reduced delayed rectifier potassium current and/or reduced BK- and SK-type calcium-dependent potassium current. Perforated patch recordings will test the possibility that an abnormal chloride or potassium gradient plays a role in cellular hyperexcitability. Additional electrophysiological studies will assess the temporal relationship between the firing of these cells and population bursts of entorhinal cortical neurons, normally-situated granule cells or CAS pyramidal cells and the possibility that these cells receive feedback excitation from CAS pyramidal cells. Pharmacotherapy of temporal lobe epilepsy usually fails to achieve long-term remission. This project will shed light on the pathophysiological role of an anatomical reorganization unique to this disorder and may uncover novel therapeutic targets. In particular, it may be advantageous to target mechanisms of hyperexcitability operative in hilar ectopic granule cells, but not in normal granule cells