Long-Term Potentiation of Mossy Fiber Feedforward Inhibition of CA3 Pyramidal Cells Maintains E/I Balance in Epilepsy Model

Insight into the cellular and circuit mechanisms underlying development of temporal lobe epilepsy (TLE) will provide a foundation for improved therapies. We studied a model in which an episode of prolonged seizures is followed by recovery lasting two weeks before emergence of spontaneous recurrent seizures. We focused on the interval between the prolonged seizures and the late onset recurrent seizures. We investigated the hippocampal mossy fiber CA3 pyramidal cell microcircuit in models spanning in vitro, in vivo, and ex vivo preparations. Expression of channelrhodopsin-2 in the dentate granule cells of DGC ChR mice enabled the selective activation of mossy fiber axons. In vivo studies revealed marked potentiation of mossy fiber evoked field potentials in hippocampal CA3 beginning within hours following seizures, a potentiation which persisted at least 7 d. Stimulation of mossy fibers in hippocampal slices in vitro using patterns of activity mimicking seizures induced LTP not only of the monosynaptic EPSC but also of the disynaptic IPSC of CA3 pyramidal cells. Ex vivo studies of slices isolated following seizures revealed evidence of LTP of mossy fiber evoked EPSC and disynaptic IPSC of CA3 pyramidal cells. We suggest that activation of dentate granule cells during seizures induces these plasticities in vivo and the retained balance of synaptic excitation and inhibition limits excessive activation of CA3 pyramidal cells, thereby protecting animals from spontaneous recurrent seizures at this interval following status epilepticus.