Postdoctoral fellow University of Texas Health San Antonio San Antonio, Texas
This abstract has been invited to present during the Better Patient Outcomes through Diversity Platform poster session This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Nearly 3 million people in the U.S. suffer traumatic brain injury (TBI) yearly. However, there are no treatment options available for after a TBI event. Seizures are very common after a TBI, making further seizures and development of epilepsy disease more likely. TBI is the cause of 5-6% of all epilepsy cases. KCNQ2-5 voltage-gated K+ channels underlie the neuronal “M-current,” which plays a dominant role in the regulation of neuronal excitability. Our strategy towards prevention of post-traumatic epilepsy (PTE) and other TBI effects is to block hyperexcitability of neurons with pharmacological augmentation of M current. We have previously shown, in blunt injury mice model, that TBI-induced seizures, metabolic stress, cell death, immunologic/inflammatory response, and blood-brain barrier leakage can be treated with one acute dose of pharmacological M-current enhancer. Methods: Here, we tested the efficacy of the proposed treatment with two different TBI models. The first is a blunt TBI mice model that simulates blunt injuries commonly observed in motorcycle accidents and sports injuries. The second is a blast TBI mouse model that uses compressed air shock waves to simulate explosion-like TBIs, such as those commonly experienced on the battlefield.In vivo two-photon imaging of [Ca2+]i in cortical neurons was performed before and after blunt TBI in mice expressing the genetically-encoded Ca2+ reporter, GCaMP6s. Another cohort of mice subjected to blunt TBI was monitored via video/EEG for the occurrence of seizures after sub-threshold stimulation with the chemoconvulsant, pentylenetetrazole (PTZ).
Mice subjected to repetitive blast injuries were monitored via video/EEG for one year to quantify the percentage of mice that developed PTE. After two years post-TBI, samples from their cortex, hippocampus and cerebellum were collected for immunoblotting and immunofluorescence analysis of expression of TAR DNA binding protein-43 (TDP-43), which has been shown to play a pathogenic role in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Results: In vivo two-photon imaging revealed blunt TBI to induce a time dependent increase in calcium spike frequency and a decrease in inter spike interval. These TBI-induced changes were reduced by acute pharmacological M-current increase. Blunt TBI also induced a decrease in the number of network burst firing events, and this effect was impaired by M-current enhancement. Additionally, post-TBI pharmacological M-current increase reduced seizure occurrence after PTZ administration. The percentage of mice that development PTE after repetitive blast TBI was reduced by pharmacological M-current increase. The same mice also presented a TBI-induced increase in cortical TDP-43 levels that was prevented by M-current treatment. Conclusions: Taken together, our results support pharmacological M-current increase as an effective post-TBI treatment that has beneficial effects that go beyond acute reduction of neuronal hyperexcitability. Funding: Please list any funding that was received in support of this abstract.: This work was supported by DoD grants (W81XWH-13/15-1-0284 and -0285) (M.S.S. and J.D.L.), an AHA postdoctoral fellowship (20POST35180050) (F.A.V.).
