Effect of Hyperoxia on Central Nervous System Intercellular Communication Mediated by Tunneling Nanotubes

Abstract

Oxygen toxicity occurs when exposure to elevated partial pressures of oxygen results in hyperoxia. Central nervous system oxygen toxicity (CNS‐OT) can culminate in seizures, and elucidating mechanisms of CNS‐OT will provide approaches for prevention, delay to onset or amelioration of hyperoxic damage. However, little is known of the pathophysiology of hyperoxia. A possible mediator is the tunneling nanotube (TnT). TnTs are thin, membranous connections mediating the transfer of intracellular materials, including proteins and organelles. We recently identified TnTs between normal brain and glioblastoma cells in mouse xenograft brain sections. When neurons or astrocytes are exposed to H2O2, stressed cells form TnTs and unidirectionally transfer materials, indicating that TnTs may be induced by stress as a defense mechanism. Therefore, we are evaluating the effect of oxygen tension on TnT formation and materials transfer and function in neurons and glia. These studies will reveal molecular changes in CNS cell connectivity. Preliminary data indicate that SK‐N‐SH cells grown in 85% oxygen produce more TnTs than cells grown in standard conditions. We also found increased expression of putative TnT markers, ezrin, cxn43, myoX and rhot1, in hyperoxic conditions. The anticonvulsant vigabatrin, which prevents hyperbaric oxygen‐induced seizures in rats, increases the number of TnTs per cell under norm‐ and hyperoxia, suggesting that vigabatrin may upregulate TnT production to facilitate the transfer of materials that protect against hyperoxia. Our studies will elucidate TnT formation and function and identify regulatory mechanisms governing TnT‐mediated behaviors following hyperoxia.