Signaling Pathways and Cellular Mechanisms Regulating Mossy Fiber Sprouting in the Development of Epilepsy

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.

Imaging biomarkers of epileptogenecity after traumatic brain injury – Preclinical frontiers

“…Mossy fiber sprouting in the dentate gyrus of the hippocampus correlates with seizure susceptibility in LFPI (Kharatishvili et al, 2007), and in SE animal models (Lowenstein et al, 1993;Mathem et al, 1993). It is one of the most consistent findings in surgical specimens from patients with mesial temporal lobe epilepsy, while the exact role in epileptogenesis is still under debate (Godale & Danzer, 2018). Axonal sprouting has been imaged in pre-clinical models by manganese enhanced MRI (MEMRI), in LFPI (Bouilleret et al, 2009) and other post insult epilepsy models such as kainic acid induced status epilepticus (Dedeurwaerdere et al, 2013;Immonen et al, 2008).…”

Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections

“…In mTLE, neurogenesis in the dentate gyrus (DG) is increased in both human patents and experimental models. Additionally, the epileptic environment promotes the sprouting of DG neurons toward the CA3 region along the mossy fiber pathway (Bausch and McNamara, 2004;Häussler et al, 2016;Godale and Danzer, 2018). The emerging consensus suggests that increased neurogenesis and neuronal sprouting are proepileptogenic (Cho et al, 2015;Hosford et al, 2016;Danzer, 2018).…”

The impact of postsynaptic density 95 blocking peptide (Tat‐NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate‐induced epileptogenesis

“…Previous studies have provided important insights into the underlying cellular and molecular processes of epileptogenesis, highlighting neuroinflammation, the innate immune response, microglial activation, synaptic reorganization, and oxidative stress as key mechanisms in this regard (Bitsika et al, ; Keck et al, , ; Li et al, ; Liu et al, ; Marques‐Carneiro et al, ; Walker et al, ). Many of these observations are unsurprising, given the burgeoning knowledge base surrounding the mechanisms and pathways believed to contribute to the development of epilepsy (Aronica et al, ; Becker, ; Godale & Danzer, ; Lukawski et al, ; Pitkänen et al, ). Our experimental design is novel with respect to the choice of two putative anti‐epileptogenic agents, that is, PSD95BP (Tat‐NR2B9c) that targets neurons and 1400W that targets the glial source of NO.…”