Perinodal glial swelling mitigates axonal degradation in a model of axonal injury.

Abstract

Mild traumatic brain injury (mTBI) has been associated with the damage to myelinated axons in white matter tracts. Animal models and in vitro studies suggest that axonal degradation develops during a latent period following a traumatic event. This delay has been attributed to slowly developing axonal membrane depolarization that is initiated by injury-induced ionic imbalance and in turn, leads to the activation of Ca(2+) proteases via pathological accumulation of Ca(2+). However, the mechanisms mitigating the transition to axonal degradation after injury remain elusive. We addressed this question in a detailed biophysical model of axonal injury that incorporated ion exchange and glial swelling mechanisms. We show that glial swelling, which often co-occurs with mTBI, promotes axonal survival by regulating extracellular K(+) dynamics, extending the range of injury parameters in which axons exhibit stable membrane potential postinjury. In addition, glial swelling was instrumental in reducing axonal sensitivity to repetitive stretch injury that occurred several minutes following the first one. Results of this study suggest that acute post-traumatic swelling of perinodal astrocytes helps prevent or postpone axonal degradation by maintaining physiologically relevant levels of extracellular K(+).