Cell-generated mechanical forces play a role in epileptogenesis after injury

Abstract

Traumatic brain injury (TBI) is associated with a significantly increased risk of epilepsy. One of the consequences of severe TBI is progressive brain atrophy, which is frequently characterized by organized tissue retraction. Retraction is an active process synchronized by mechanical interactions between surviving cells. This results in unbalanced mechanical forces acting on surviving neurons, potentially activating mechanotransduction and leading to hyperexcitability. This novel mechanism of epileptogenesis was examined in organotypic hippocampal cultures, which develop spontaneous seizure-like activity in vitro. Cell-generated forces in this model resulted in contraction of hippocampal tissue. Artificial imbalances in mechanical forces were introduced by placing cultured slices on surfaces with adhesive and non-adhesive regions. This modeled disbalance in mechanical forces that may occur in the brain after trauma. Portions of the slices that were not stabilized by substrate adhesion underwent increased contraction and compaction, revealing the presence of cell-generated forces capable of shaping tissue geometry. Changes in tissue geometry were followed by excitability changes that were specific to hippocampal sub-region and orientation of contractile forces relative to pyramidal cell apical-basal axis. Results of this study suggest that imbalanced cell-generated forces contribute to development of epilepsy, and that force imbalance may represent a novel mechanism of epileptogenesis after trauma.