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.

Julian Tejada,Norberto Garcia-Cairasco,Antonio C Roque

doi:10.1371/journal.pcbi.1003601

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.

Highlights

Several evidences have shown that prolonged seizures such as those in the animal models of Status Epilepticus (SE) induced by kainic acid or pilocarpine [1] act as a strong insult with consequent anatomical and functional sequelae
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 or decreasing the activity in the network

Summary

Introduction

Several evidences have shown that prolonged seizures such as those in the animal models of Status Epilepticus (SE) induced by kainic acid or pilocarpine [1] act as a strong insult with consequent anatomical and functional sequelae. There is still some controversy on how much each one of these alterations contributes to epileptogenesis, it is clear that multivariate interactions are needed for the full appearance of the chronic state with spontaneous recurrent seizures (SRS) [9] These models replicate cellular and molecular plastic alterations, besides epileptiform EEG features observed in clinical TLE [10,11,12]. DG GCs present a series of morphological and anatomical alterations induced by temporal lobe epilepsy (TLE) [6,7,13,14,15,16,17] Their axons sprout collaterals directed towards the DG molecular layer and make recurrent excitatory synapses with other GCs (this phenomenon is called MFS) [2,6]. In parallel with these morphological alterations, TLE induces a higher rate of neurogenesis of DG GCs [20,21]

Objectives

Methods

Results

Discussion

Conclusion