Combined Role of Seizure-Induced Dendritic Morphology Alterations and Spine Loss in Newborn Granule Cells with Mossy Fiber Sprouting on the Hyperexcitability of a Computer Model of the Dentate Gyrus

Abstract

Temporal lobe epilepsy strongly affects hippocampal dentate gyrus granule cells morphology. These cells exhibit seizure-induced anatomical alterations including mossy fiber sprouting, changes in the apical and basal dendritic tree and suffer substantial dendritic spine loss. The effect of some of these changes on the hyperexcitability of the dentate gyrus has been widely studied. For example, mossy fiber sprouting increases the excitability of the circuit while dendritic spine loss may have the opposite effect. However, the effect of the interplay of these different morphological alterations on the hyperexcitability of the dentate gyrus is still unknown. Here we adapted an existing computational model of the dentate gyrus by replacing the reduced granule cell models with morphologically detailed models coming from three-dimensional reconstructions of mature cells. The model simulates a network with 10% of the mossy fiber sprouting observed in the pilocarpine (PILO) model of epilepsy. Different fractions of the mature granule cell models were replaced by morphologically reconstructed models of newborn dentate granule cells from animals with PILO-induced Status Epilepticus, which have apical dendritic alterations and spine loss, and control animals, which do not have these alterations. This complex arrangement of cells and processes allowed us to study the combined effect of mossy fiber sprouting, altered apical dendritic tree and dendritic spine loss in newborn granule cells on the excitability of the dentate gyrus model. Our simulations suggest that alterations in the apical dendritic tree and dendritic spine loss in newborn granule cells have opposing effects on the excitability of the dentate gyrus after Status Epilepticus. Apical dendritic alterations potentiate the increase of excitability provoked by mossy fiber sprouting while spine loss curtails this increase.

Author Summary

Neurogenesis is currently a well known phenomenon in the adult brain, in special in some areas such as the subventricular zone and the dentate gyrus in the hippocampus, in which different endogenous and exogenous factors provoke cell proliferation. In the specific case of the dentate gyrus, granule cells proliferate exhibiting altered morphology after the induction of Status Epilepticus (SE) by pilocarpine (PILO). Several days after the injury the new cells show different morphological alterations, for example, in dendritic spines and branching patterns, as well as with the formation of axonal sprouting. The way in which these new cells are integrated into the hippocampus is still unknown with conflicting data in the literature. Here we used computer simulation to test if the activity of the dentate gyrus is affected by the presence of different proportions of new cells after PILO-induced SE. Our results show that the specific morphological alterations present in the granule cells in rats with PILO-induced SE may be responsible for increasing (mossy fiber sprouting) or decreasing (spine loss) the activity in the network. The imbalance between these effects may be manifest as an epileptiform network behavior.