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.

Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke–Korsakoff syndrome

“…Therefore, it is possible that this high sensitivity to excitotoxicity leads to loss of neurons and spines in the hippocampus of PTD mice. Moreover, seizures and neurodegenerative diseases such as Alzheimer’s disease causes dendritic spine abnormality including spine loss in the DG neurons, 68–70 ) raising the possibility that dendritic spines in DG neurons are susceptible to pathological damages by PTD. It is important to examine whether neural degeneration at the cellular, synaptic, and spine levels occurs in the hippocampus of WKS cases.…”

The Ever-Changing Morphology of Hippocampal Granule Neurons in Physiology and Pathology

“…The abnormal basal dendrites form additional recurrent synapses with the aberrant axonal collaterals of the MF, thus aggravating the recurrent nature of the circuit (Patel et al, 2004 ). Although not all the experimental data support the idea of individual cell hyper-excitability in epilepsy (Patel et al, 2004 ), computational (Tejada et al, 2012 , 2014 ) and in vitro (Beck et al, 1996 ; Bausch and McNamara, 2000 ) models do strongly reinforce this notion. In addition, the electrophysiological properties of granule cells aberrantly located in the hilar region were studied in a rat model of TLE and in epileptic patients by Althaus et al The authors found an increased excitability in rat neurons whereas neurons obtained from patients displayed a clear reduction in excitability.…”

Modeling the influence of heavy ion beams on neurogenesis and functioning of hippocampal neural networks

“…In the SGZ, newly born neurons migrate into the DG granule cell layer and mature, connecting it with the CA3 region of the hippocampus. The influence of immature granular cells (ImN) on network performance was implemented according to the model of posttraumatic DG activity [6]. It follows that the increase of the number of newborn granular neurons enhances network excitability, and, thus, newborn neuron loss following irradiation will likely suppress the network activity.…”