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1 Anatomy & Neurobiology, University of California - Irvine, Irvine, California, United States
2 Anatomy & Neurobiology, University of California - Irvine, Irvine, California, United States; United States
3 Inst. for Nonlinear Science, University of California - San Diego, San Diego, California, United States
* To whom correspondence should be addressed. E-mail: jdyhrfje{at}uci.edu.
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 1 million cells was less than 3, 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, due to spatially restricted sprouting of granule cell axons, local connectivity increased. Simulations of activity in a functional dentate network model, consisting of over 50,000 multi-compartmental single cell models of major glutamatergic and GABAergic cell types, revealed that the survival of even a small fraction of hilar cells was enough to sustain network-wide hyperexcitability. These data indicate new roles for fractionally surviving long-distance projecting hilar cells observed in specimens from epilepsy patients.
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