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Page 236 Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02

Figure 1. Granule cell neurogenesis and mossy fiber sprouting. A: Neurogenesis occurs in the dentate gyrus of the hippocampus.
The cells proliferate in the subgranular zone and then migrate a short distance to the granule cell layer where they differentiate into
mature granule cells; B: the axons of granule cells (mossy fibers) normally project to the cells in the CA3 region of the dentate gyrus;
C: during seizures, several factors contribute to aberrant migration of granule cells that leads to their ectopic placement in the hilus.
Ectopic granule cells (red cells) form functioning neural connections to the pyramidal neurons in the CA3 region and contribute to
hyperexcitability and epileptogenesis through aberrant ‘sprouting’ along the mossy fiber pathway. Image created with BioRender.com

[14]
[15]
patients . Though originally believed to result in an increase in levels of GABA production , there may
[16]
be multiple mechanisms that contribute to its success in seizure cessation . Neurostimulatory devices,
such as deep brain or vagus nerve stimulation therapies, have also been used with varying success, as they
[17]
help to normalize the excitatory state of the brain .
Epileptogenesis
Epileptogenesis is the process by which structural and molecular changes occur in the brain and predispose
[18]
towards epileptic seizures . The epileptogenic process can be initiated by multiple underlying causes such
as tumors, infections, stroke, and brain injuries. Epileptogenesis occurs prior to an unprovoked seizure
and continues beyond the event. It is a dynamic process that can occur very quickly, after brain injury or
stroke, or over an extended period of time (up to months in animal models, and years in humans) [18,19] .
This window presents a temporal opportunity for treatment approaches, but also provides challenges for
studying the process. Understanding the pathophysiological changes that occur during epileptogenesis is a
pivotal part of developing new therapies.

Changes during epileptogenesis occur in both neuronal and glial cells, all of which contribute to
the dysfunction of neuronal circuits. The mechanisms underlying epileptogenesis suggest that the
pathophysiological and compensatory changes are connected. Animal models of epileptogenesis have
displayed histologically-detectable changes, such as sprouting along the mossy fiber pathway, neurogenesis,
[20]
and gliosis [Figure 1] alterations, all of which can contribute to the potential for hyperexcitability . The
condition most frequently associated with mossy fiber sprouting is temporal lobe epilepsy (TLE), the