The objective of this project is to investigate traumatic brain injury (TBI)-induced seizures. Specifically, we will use TrkB, EphrinBS and EphB3/A4 knockout mice, as well as specific BDNF and EphrinB scavengers, to study molecular mechanisms and treatment of post-TBI seizures. Despite their clinical importance, post-TBI seizures have been largely understudied. In fact, there have been fewer than 10 experimental animal stijdies of cellular mechanisms of post-TBI seizures during the last decade, which is in striking contrast with the several thousands of publications on kindling seizures. In addition to the enormous gap between the seizure and TBI research fields, the lack of studies may also be because there were limited molecular and technical approaches to tackle this serious clinical problem. We have found dramatic cytoskeleton-related synaptic alterations in seizure-prone brain regions after TBI. Our new studies have also cleariy demonstrated that BDNF and Ephrin activities are drastically upregulated in seizure-prone brain regions after TBI. The BDNF/TrkB and Ephrin/Eph pathways control actin-dependent synaptic organization. In this proposal, we will test the hypothesis that sustained recurrence of post-TBI seizures is a consequence of overactivation of BDNF/TrkB- and/or EphrinB/EphB-mediated aberrant synaptic reorganization.
Aim 1 will investigate whether activation of BDNF/TrkB and/or EphrinB/EphB is required for the development of post-TBI seizures, by means of TrkB, EphrinBS and EphB3/A4 KO mice;
Aim 2 will study the BDNF/TrkB and/or EphrinB/EphB signaling pathways leading to enhanced seizure susceptibility after TBI;
and Aim 3 will explore tTrkB-Fc or tEphrin-Fc chimeric reagents treatments of seizure susceptibility after TBI.

Public Health Relevance

Please refer to proposal page '2'for overall project relevance to public health.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Miami School of Medicine
Coral Gables
United States
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Blaya, Meghan O; Tsoulfas, Pantelis; Bramlett, Helen M et al. (2015) Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp Neurol 264:67-81
Theus, M H; Ricard, J; Glass, S J et al. (2014) EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury. Cell Death Dis 5:e1207
Baumann, Gisela; Travieso, Lissette; Liebl, Daniel J et al. (2013) Pronounced hypoxia in the subventricular zone following traumatic brain injury and the neural stem/progenitor cell response. Exp Biol Med (Maywood) 238:830-41
Park, Yujung; Luo, Tianfei; Zhang, Fan et al. (2013) Downregulation of Src-kinase and glutamate-receptor phosphorylation after traumatic brain injury. J Cereb Blood Flow Metab 33:1642-9
Zhang, Fan; Guo, Ailan; Liu, Chunli et al. (2013) Phosphorylation and assembly of glutamate receptors after brain ischemia. Stroke 44:170-6
Atkins, Coleen M; Cepero, Maria L; Kang, Yuan et al. (2013) Effects of early rolipram treatment on histopathological outcome after controlled cortical impact injury in mice. Neurosci Lett 532:1-6
Sabirzhanova, Inna; Liu, Chunli; Zhao, Jingwei et al. (2013) Changes in the GEF-H1 pathways after traumatic brain injury. J Neurotrauma 30:1449-56
Truettner, Jessie S; Motti, Dario; Dietrich, W Dalton (2013) MicroRNA overexpression increases cortical neuronal vulnerability to injury. Brain Res 1533:122-30
Mawhinney, Lana J; de Rivero Vaccari, Juan Pablo; Alonso, Ofelia F et al. (2012) Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain. Brain Res 1431:23-34
Bregy, Amade; Nixon, Ryan; Lotocki, George et al. (2012) Posttraumatic hypothermia increases doublecortin expressing neurons in the dentate gyrus after traumatic brain injury in the rat. Exp Neurol 233:821-8

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