Epileptogenesis in the dentate gyrus: a critical perspective.

The dentate gyrus has long been a focal point for studies on the molecular, cellular, and network mechanisms responsible for epileptogenesis in temporal lobe epilepsy (TLE). Although several hypothetical mechanisms are considered in this chapter, two that have garnered particular interest and experimental support are: (1) the selective loss of vulnerable interneurons in the region of the hilus and (2) the formation of new recurrent excitatory circuits after mossy fiber sprouting. Histopathological data show that specific GABAergic interneurons in the hilus are lost in animal models of TLE, and several lines of electrophysiological evidence, including intracellular analyses of postsynaptic currents, support this hypothesis. In particular, whole-cell recordings have demonstrated a reduction in the frequency of miniature inhibitory postsynaptic currents in the dentate gyrus and other areas (e.g., CA1 pyramidal cells), which provides relatively specific evidence for a reduction in GABAergic input to granule cells. These studies support the viewpoint that modest alterations in GABAergic inhibition can have significant functional impact in the dentate gyrus, and suggest that dynamic activity-dependent mechanisms of GABAergic regulation add complexity to this local synaptic circuitry and to analyses of epileptogenesis. In regard to mossy fiber sprouting, a wide variety of experiments involving intracellular or whole-cell recordings during electrical stimulation of the hilus, glutamate microstimulation, and dual recordings from granule cells support the hypothesis that mossy fiber sprouting forms new recurrent excitatory circuits in the dentate gyrus in animal models of TLE. Similar to previous studies on recurrent excitation in the CA3 area, GABA-mediated inhibition and the intrinsic high threshold of granule cells in the dentate gyrus tends to mask the presence of the new recurrent excitatory circuits and reduce the likelihood that reorganized circuits will generate seizure-like activity. How cellular alterations such as neuron loss in the hilus and mossy fiber sprouting influence functional properties is potentially important for understanding fundamental aspects of epileptogenesis, such as the consequences of primary initial injuries, mechanisms underlying network synchronization, and progression of intractability. The continuous nature of the axonal sprouting and formation of recurrent excitation could account for aspects of the latent period and the progressive nature of the epileptogenesis. Future studies will need to identify precisely how these hypothetical mechanisms and others contribute to the process whereby epileptic seizures are initiated or propagated through an area such as the dentate gyrus. Finally, in addition to its unique features and potential importance in epileptogenesis, the dentate gyrus may also serve as a model for other cortical structures in acquired epilepsy.