Factors contributing to Post-Traumatic Dentate Hyperexcitability: A Network Model Incorporating Topographic Connectivity Patterns

Abstract

Head injury is a major risk factor in the etiology of temporal lobe epilepsy (TLE). Studies using a rodent model of concussive head trauma have identified specific patterns of cell loss and synaptic reorganization in the dentate gyrus after brain injury, which are similar to the changes in human TLE. However, the contribution of each of these cellular and synaptic alterations to increased excitability in the dentate neuronal circuits is not known. In order to independently examine the factors critical to post-traumatic dentate bhyperexcitability, we developed a reduced network model of the dentate gyrus with 500 granule cells, 15 mossy cells 6 basket cells and 6 hilar interneurons. The topographic networks were constructed with connectivity patterns constrained by the spatial distribution of the axonal arbors of the cell types. Sprouting was simulated by addition of mossy fiber to granule cell connections with the maximum sprouting (100%) estimated from the distribution of sprouted axons in a rodent model of spontaneous recurrent seizures (Buckmaster and Dudek 1999). Simulations were performed using NEURON (Hines 1993). Our results show that perforant path stimulation evoked greater granule cell firing in the dentate excitatory network with as low as 10% sprouting compared to the control topographic network. Additionally, the topographic network was more hyperexcitable than the non-topographic network with the same degree of sprouting. Mossy cell loss decreased the spread of hyperexcitability in the network 10% sprouting. With increasing sprouting, even the complete loss of mossy cells was unable to prevent the spread of hyperexcitability. Simulations of both purely excitatory network and the full network showed that mossy fiber sprouting was sufficient to elicit hyperexcitable perforant path evoked responses in all cell types examined. Mossy cell loss was neither necessary nor sufficient to cause granule cell hyperexcitability in the dentate network with inhibition. The network simulations show that mossy fiber sprouting can contribute to increased excitability in the dentate gyrus even in the absence of cell loss or changes in the intrinsic properties of the cells. The data from the topographically constrained simulations indicate that the lamellar topology of the sprouted mossy fibers is important for the spread of granule cell excitability. The results suggest that the moderate sprouting observed after concussive head trauma is likely to be a major factor in post-traumatic dentate hyperexcitability. Acknowledgment: Supported by the NIH (NS35915) to I.S.