Abstract

The sprouting of hippocampal dentate granule cell axons, termed mossy fibers, into the dentate inner molecular layer is one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy. Decades of research in animal models have revealed that mossy fiber sprouting creates de novo recurrent excitatory connections in the hippocampus, fueling speculation that the pathology may drive temporal lobe epileptogenesis. Conducting definitive experiments to test this hypothesis, however, has been challenging due to the difficulty of dissociating this sprouting from the many other changes occurring during epileptogenesis. The field has been largely driven, therefore, by correlative data. Recently, the development of powerful transgenic mouse technologies and the discovery of novel drug targets has provided new tools to assess the role of mossy fiber sprouting in epilepsy. We can now selectively manipulate hippocampal granule cells in rodent epilepsy models, providing new insights into the granule cell subpopulations that participate in mossy fiber sprouting. The cellular pathways regulating this sprouting are also coming to light, providing new targets for pharmacological intervention. Surprisingly, many investigators have found that blocking mossy fiber sprouting has no effect on seizure occurrence, while seizure frequency can be reduced by treatments that have no effect on this sprouting. These results raise new questions about the role of mossy fiber sprouting in epilepsy. Here, we will review these findings with particular regard to the contributions of new granule cells to mossy fiber sprouting and the regulation of this sprouting by the mTOR signaling pathway.

Highlights

  • Many investigators have found that blocking mossy fiber sprouting has no effect on seizure occurrence, while seizure frequency can be reduced by treatments that have no effect on this sprouting

  • In laboratory animals modeling mesial temporal lobe epilepsy, mossy fiber axon reorganization can occur in all of the hippocampal subfields normally targeted by granule cells [6,7,8,9,10,11,12]

  • Mossy Fiber Sprouting in Epilepsy projections, granule cell axons add an additional target to their repertoire: the inner molecular layer of the dentate gyrus [13,14,15,16,17,18]

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Summary

Signaling Pathways and Cellular Mechanisms Regulating

Mossy Fiber Sprouting in the Development of Epilepsy. Front. In laboratory animals modeling mesial temporal lobe epilepsy (mTLE), mossy fiber axon reorganization can occur in all of the hippocampal subfields normally targeted by granule cells [6,7,8,9,10,11,12]. Granule cell mossy fiber axons sprout, projecting new collaterals to the inner molecular layer, where they form excitatory synaptic connections with the proximal portions of the granule cell dendritic trees [23, 24]. The mechanisms regulating the specificity of mossy fiber sprouting have yet to be elucidated

FUNCTIONAL SIGNIFICANCE OF MOSSY FIBER SPROUTING IN EPILEPSY
IMPACT OF ABLATING NEWBORN CELLS ON MOSSY FIBER SPROUTING
REGULATION OF MOSSY FIBER SPROUTING BY mTOR
Findings
THERAPEUTIC IMPLICATIONS
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