NSC Thesis Proposal: Xiaowei Wang
Na+-K+-Cl- Cotransporter-1 Up-regulation Mediates Early Seizure Activities Following Traumatic Brain Injury
Monday, October 7
Professor Jason H. Huang, M.D., Ph.D., M.P.D.
Traumatic brain injury (TBI) is a major risk factor for post-traumatic seizures (PTS). Reports indicate that after severe brain injury the risk for developing PTS is 17-20 percent. Neurons accumulate Cl- through the action of the Na+-K+-2Cl- cotransporter (NKCC1, encoded by SLC12A2). NKCC1 expression is high during early central nervous system (CNS) development and has been shown to be involved in neonatal seizures. The basis for this proposal is that the post-injury edematous brain is highly seizure prone. We speculate that dysregulation of NKCC1 and K+-Cl--cotransporter 2(KCC2) after TBI may contribute to the reduced threshold for seizures by increasing intraneuronal Cl- concentration ([Cl-]i). An increased [Cl-]i renders GABAergic input less inhibitory, which may lead to seizures. The main objective of this project is thus to elucidate whether dysregulation of NKCC1 and KCC2 after TBI can lead to post-traumatic seizure. To achieve this goal, a PTS mouse model recently developed in our lab will be utilized. Consistent injury-induced seizures have been observed in this model. Following the injury, 37% of injured wild type animals exhibited violent convulsion, 27% of them had extended limbs with multiple jerks, and 24% of them showed milder seizure signs. The remaining 12% behave normal during our observation. In Aim 1, we will use Western blot and immunofluorescent labeling to characterize the effect of TBI on the expression of NKCC1 and KCC2 after TBI and compare the results with that from both sham operated controls and injured animals that did not have seizure. We will also determine whether injury-induced change in transporters expression is causally involved in the post-traumatic seizures. This will be tested by evaluating the reversal potential of GABA-evoked chloride current in mice with PTS in comparison with animals exposed to traumatic injury that did not develop PTS and in sham operated controls. In Aim 2, we will determine whether deletion or inhibition of NKCC1 decreases the seizure prevalence in our PTS model. To this end, we will test whether genetic knockout and pharmacological blockade of NKCC1 can reduce PTS. Mice in this experiment will be monitored for behavioral and electrophysiological signs of seizure combined video-EEG. These studies will advance our understanding of NKCC1's role in post-traumatic seizure; positive findings from our studies could help to identify novel therapeutic targets for management of TBI induced seizures.
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Sneak Peak of The Brain with Dr. David Eagleman at The Little Theater Followed by Panel Discussion Featuring Liz Romanski