Adult-Born Neurons and the Development of Posttraumatic Epilepsy
Abstract
Traumatic brain injury (TBI) causes multiple long-term disabilities, including an increased risk of subsequently developing epilepsy. It is unclear how seizures develop after TBI, although it is likely that neuronal circuit rearrangements in the brain are responsible. After non-trauma-related seizures, new neurons are born in the adult hippocampus in an accelerated manner. These adult-born neurons grow abnormally in a number of distinctive ways, including the backward sprouting of their mossy fiber axons, which may contribute to the development of epilepsy. Our preliminary data demonstrate that adult-born neurons also grow abnormally after TBI, and we would like to test the hypothesis that these newborn neurons contribute to the development of post-traumatic epilepsy. This would be a paradigm shift in our appreciation of post-traumatic neurogenesis, which is otherwise widely considered to be a beneficial response that contributes to cognitive recovery after injury. We propose to use novel combinations of transgenic mice to label adult-born neurons and to study how TBI alters their network connectivity. We propose to test the hypothesis that adult-born neurons specifically give rise to aberrant circuits after TBI by examining the neuronal inputs and outputs formed by these cells, using both structural and functional assays. Additionally, we will use genetic tools to alter electrical activity in these adult-born neurons, which will allow us to functionally determine whether these new cells alter excitability in the hippocampus. Finally, we will test whether the administration of benzodiazepines early after TBI, which our preliminary data suggests normalizes the maturation of adult-born neurons after injury, prevents the development of epilepsy. Overall, this project has the potential to dramatically re-frame our understanding of neurogenesis after TBI and will test a clinically translatable approach to optimize the management of humans after head injury, with the goal of preventing the development of epilepsy. We are very optimistic that these experiments will also advance our understanding of non-trauma-related epilepsy, allowing us to work towards the goal of preventing the development of epilepsy in susceptible patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810598
Entities
People
- Eric Schnell
Organizations
- Oregon Health & Science University
- United States Army