Localized network hyperconnectivity leads to hyperexcitability after injury

Brain injury increases the risk of the development of epilepsy. Axonal sprouting and synaptogenesis are homeostatically mediated responses by neurons to injury-induced de-afferentation and de-efferentation. Rewiring which occurs due to axonal sprouting and synaptogenesis may alter network excitability and lead to epilepsy. Excitatory and inhibitory connectivity are both subject to homeostatic rewiring. Thus, post-sprouting hyperexcitability cannot be simply explained as result of altered inhibitory/excitatory balance. In this work, we show computationally and experimentally that hyperconnected local networks are created by homeostatic rewiring near the injury site. These local networks are characterized by altered system dynamics despite preservation of excitatory/inhibitory balance. Hyperconnected local networks have a lower threshold for burst initiation, and generate spontaneous bursts, which in turn ignite seizure-like activity in the larger network. Our findings demonstrate a novel network mechanism of hyperexcitability and seizure generation due to maladaptive recovery after injury.