Recurrent mossy fiber sprouting in the hippocampal dentate gyrus is a unique feature of temporal lobe epilepsy. The formation of new mossy fiber-granule cell connection rates circuitry that is presumably capable of supporting reverberating excitation, similar to the recurrent excitatory circuitry normally present in area CA3 of the hippocampus. By analogy with area CA3, the development of new recurrent circuitry in the epileptic brain may facilitate granule cell synchronization and diminish the normally high resistance of the dentate gyrus toward seizure propagation. Pilocarpine-treated rats, which become epileptic and also develop a consistently dense recurrent mossy fiber pathway, will be used to test this hypothesis. In area CA3, epileptiform activity is thought to be initiated by the synchronized firing of a small number of pyramidal cells. These """"""""detonator"""""""" cells are considered to be more rapidly excited than other cells in the population. A minority of granule cells have unusually large recurrent mossy fiber EPSCs and a minority also develop a basal dendrite innervated by recurrent mossy fibers. The proposed studies will determine whether these two neuronal populations overlap. If they do, then granule cells with a basal dendrite would be candidates for the role of detonator cell in the dentate gyrus of epileptic brain. In area CA3, the effect of recurrent excitatory circuitry is normally suppressed by among other factors, GABA inhibition and inhibitory K+ conductance. The proposed studies will determine whether and how readily frequency facilitation, elevated extracellular K+, reduced GABA inhibition and block of inhibitory metabotropic glutamate receptors unmask recurrent mossy fiber pathway actually does enhance propagation of epileptiform discharge through the dentate gyrus. In addition, glutamate receptors expressed by the mossy fiber pathway will be evaluated for their involvement in granule cell epileptic activity. These studies will provide pharmacological tools to separate the effect of recurrent mossy fiber growth from that of other possible changes in the epileptic dentate gyrus, and they may also suggest novel approaches to pharmacotherapy.
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