Oxidation of KCNB1 potassium channels causes neurotoxicity and cognitive impairment in a mouse model of traumatic brain injury

Wei Yu, Randika Parakramaweera, Shavonne Teng, Manasa Gowda, Yashsavi Sharad, Smita Thakker-Varia, Janet Alder, Federico Sesti

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


The delayed rectifier potassium (K+) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidizedKCNB1channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress. Dasatinib, a Food and Drug Administration–approved inhibitor of Src tyrosine kinases, was used to impinge on the proapoptotic signaling pathway activated by oxidized KCNB1 channels. Thus, typical lesions of brain injury, namely, inflammation (astrocytosis), neurodegeneration, and cell death, were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals. Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris water maze) assays compared to controls. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains. Together, these data demonstrate that oxidation of KCNB1 channels is a contributing mechanism to cellular and behavioral deficits in vertebrates and suggest a new therapeutic approach to TBI.

Original languageEnglish (US)
Pages (from-to)11084-11096
Number of pages13
JournalJournal of Neuroscience
Issue number43
StatePublished - Oct 26 2016

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)


  • Aging
  • Dasatinib
  • Kv2.1
  • Oxidative stress
  • ROS
  • Src kinases


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