The Molecular and Cellular Mechanisms of Axon Guidance in Mossy Fiber Sprouting.

Ryuta Koyama,Yuji Ikegaya

doi:10.3389/fneur.2018.00382

Abstract

The question of whether mossy fiber sprouting is epileptogenic has not been resolved; both sprouting-induced recurrent excitatory and inhibitory circuit hypotheses have been experimentally (but not fully) supported. Therefore, whether mossy fiber sprouting is a potential therapeutic target for epilepsy remains under debate. Moreover, the axon guidance mechanisms of mossy fiber sprouting have attracted the interest of neuroscientists. Sprouting of mossy fibers exhibits several uncommon axonal growth features in the basically non-plastic adult brain. For example, robust branching of axonal collaterals arises from pre-existing primary mossy fiber axons. Understanding the branching mechanisms in adulthood may contribute to axonal regeneration therapies in neuroregenerative medicine in which robust axonal re-growth is essential. Additionally, because granule cells are produced throughout life in the neurogenic dentate gyrus, it is interesting to examine whether the mossy fibers of newly generated granule cells follow the pre-existing trajectories of sprouted mossy fibers in the epileptic brain. Understanding these axon guidance mechanisms may contribute to neuron transplantation therapies, for which the incorporation of transplanted neurons into pre-existing neural circuits is essential. Thus, clarifying the axon guidance mechanisms of mossy fiber sprouting could lead to an understanding of central nervous system (CNS) network reorganization and plasticity. Here, we review the molecular and cellular mechanisms of axon guidance in mossy fiber sprouting by discussing mainly in vitro studies.

Highlights

Dentate granule cells project unmyelinated axons, i.e., mossy fibers, through the dentate hilus to the CA3 region of the hippocampus [1]
Repulsive guidance molecule a (RGMa), whose expression was high in the granule cell layer, blocked activity-dependent mossy fiber sprouting in hippocampal slice cultures by preventing the sprouted collaterals from invading the inner molecular layer [65]
That the axon guidance molecules described in the present review may affect other axons or synapses and induce mossy fiber sprouting in response

Summary

Introduction

Dentate granule cells project unmyelinated axons, i.e., mossy fibers, through the dentate hilus to the CA3 region of the hippocampus [1]. Several axon guidance cues act together to regulate the mossy fiber projections, under some epileptic conditions, the mossy fiber collaterals robustly branch out of the hilus and aberrantly, or reversely, project to the inner third of the molecular layer, in which the mossy fibers form excitatory synapses primarily on the granule cell dendrites [12,13,14,15]. In addition to these steps, we will mention the foundation for the development of mossy fiber sprouting in the dentate gyrus and the contribution of adult-born granule cells to mossy fiber sprouting.

Results

Conclusion