Recurrent mossy fiber growth in the hippocampal dentate gyrus is a unique feature of temporal lobe epilepsy. The formation of new mossy fiber-granule cell connections greatly expands a monosynaptic recurrent excitatory circuit that is normally very limited. It has been proposed that the circuit contributes to epileptogenesis by diminishing the resistance of the dentate gyrus to seizure propagation. The objective of this project is to discover the conditions under which these synapses are most likely to facilitate seizure propagation and to identify synaptic properties that could serve as therapeutic targets. Little is currently known about the physiology and pharmacology of mossy fiber- granule cell synapses; the proposed project is intended to fill this gap. Pilocarpine-treated rats, which become epileptic and also develop a consistently dense recurrent mossy fiber pathway, will be used to investigate three aspects of synaptic function. First, the characteristics of and the conditions needed to provoke three forms of presynaptic plasticity identified at mossy fiber-CA3 pyramidal cell synapses will be determined for the recurrent mossy fiber pathway. These studies will define the patterns of granule cell activity that are most likely to drive strong monosynaptic feedback excitation. Because preliminary results suggest that pilocarpine-induced status epilepticus enhances the contribution of NMDA receptors to the synaptic response, another study will determine whether mossy fiber-granule cell synapse on the epileptic brain exhibit an NMDA-dependent form of long term potentiation. Second, the involvement of kainate and metabotropic glutamate receptors to the synaptic response will be analyzed. One goal of this study is to evaluate these receptors as potential therapeutic targets of drugs directed against the recurrent mossy fiber pathway. Finally, the ability of zinc released by mossy fiber stimulation to alter GABA/A, NMDA, AMPA and kainate receptor function in granule cells will be assessed with use of agonists uncaged by highly focused ultraviolet light. This study will determine whether recurrent mossy fibers might also influence seizures through modification of postsynaptic glutamate receptors.
