Increased Expression of K_Na1.2 Channel by MAPK Pathway Regulates Neuronal Activity Following Traumatic Brain Injury

Recent studies have indicated that functional abnormalities in the K_Na1.2 channel are linked to epileptic encephalopathies. However, the role of K_Na1.2 channel in traumatic brain injury (TBI) remains limited. We collected brain tissue from the TBI mice and patients with post-traumatic epilepsy (PTE) to determine changes in K_Na1.2 channel following TBI. We also investigated whether the MAPK pathway, which was activated by the released cytokines after injury, regulated K_Na1.2 channel in in vitro. Finally, to elucidate the physiological significance of K_Na1.2 channel in neuronal excitability, we utilized the null mutant-Kcnt2^-/- mice and compared their behavior patterns, seizure susceptibility, and neuronal firing properties to wild type (WT) mice. TBI was induced in both Kcnt2^-/- and WT mice to investigate any differences between the two groups under pathological condition. Our findings revealed that the expression of K_Na1.2 channel was notably increased only during the acute phase following TBI, while no significant elevation was observed during the late phase. Furthermore, we identified the released cytokines and activated MAPK pathway in the neurons after TBI and confirmed that K_Na1.2 channel was enhanced by the MAPK pathway via stimulation of TNF-α. Subsequently, compared to WT mice, neurons from Kcnt2^-/- mice showed increased neuronal excitability and Kcnt2^-/- mice displayed motor deficits and enhanced seizure susceptibility, which suggested that K_Na1.2 channel may be neuroprotective. Therefore, this study suggests that enhanced K_Na1.2 channel, facilitated by the inflammatory response, may exert a protective role in an acute phase of the TBI model.