Increased Expression of K Na 1.2 Channel by MAPK Pathway Regulates Neuronal Activity Following Traumatic Brain Injury

Recent studies have indicated that functional abnormalities in the K Na 1.2 channel are linked to epileptic encephalopathies. However, the role of K Na 1.2 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 Na 1.2 channel following TBI. We also investigated whether the MAPK pathway, which was activated by the released cytokines after injury, regulated K Na 1.2 channel in in vitro. Finally, to elucidate the physiological significance of K Na 1.2 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 Na 1.2 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 Na 1.2 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 Na 1.2 channel may be neuroprotective. Therefore, this study suggests that enhanced K Na 1.2 channel, facilitated by the inflammatory response, may exert a protective role in an acute phase of the TBI model.