Topological determinants of epileptogenesis in large-scale structural and functional models of the dentate gyrus derived from experimental data

In temporal lobe epilepsy, changes in synaptic and intrinsic properties occur on a background of altered network architecture resulting from cell loss and axonal sprouting. Although modeling studies using idealized networks indicated the general importance of network topology in epilepsy, it is unknown whether structural changes that actually take place during epileptogenesis result in hyperexcitability. To answer this question, we built a 1:1 scale structural model of the rat dentate gyrus from published in vivo and in vitro cell type-specific connectivity data. This virtual dentate gyrus in control condition displayed globally and locally well connected ("small world") architecture. The average number of synapses between any two neurons in this network of over one million cells was less than three, similar to that measured for the orders of magnitude smaller C. elegans nervous system. To study how network architecture changes during epileptogenesis, long-distance projecting hilar cells were gradually removed in the structural model, causing massive reductions in the number of total connections. However, as long as even a few hilar cells survived, global connectivity in the network was effectively maintained and, as a result of the spatially restricted sprouting of granule cell axons, local connectivity increased. Simulations of activity in a functional dentate network model, consisting of over 50,000 multicompartmental singlecell models of major glutamatergic and GABAergic cell types, revealed that the survival of even a small fraction of hilar cells was enough to sustain networkwide hyperexcitability. These data indicate new roles for fractionally surviving long-distance projecting hilar cells observed in specimens from epilepsy patients.