Reduced GABAergic Tonic Inhibition as a Shared Mechanism of Post-Traumatic Sleep Disorders and Epilepsy
Abstract
This proposal impacts the topic area of Sleep Disorders included in the Department of Defense Peer Reviewed Medical Research Program 2016 request for applications. Traumatic brain injury (TBI) is a common problem in civilians and military personnel alike, with over 1.5 million new cases each year and over 5 million people living in the United States currently with TBI-related disability. TBI is also the signature injury in Veterans from Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn. TBI can lead to variety of sequelae that include post-traumatic epilepsy (PTE), motor and sensory problems, sleep disorders, and post-traumatic stress disorder. PTE can start immediately or long after the injury, and patients are often refractory to medications. Similarly, sleep disruptions last long after the TBI and can exacerbate underlying seizures in people with epilepsy and exacerbate psychiatric sequelae after TBI. However, not all survivors of TBI develop PTE or sleep disorders, and currently it is not possible to predict who will develop these complications. Moreover, there is also a major knowledge gap in understanding the cellular and network mechanisms underlying such sequelae. A better understanding of mechanisms of the sequelae following TBI could help develop preventive treatments for these common problems. This application will focus on whether post-traumatic sleep disorders and PTE evolve following TBI sharing a common mechanism in the brain. The focus of this study is to examine a specific mechanism called GABAergic tonic inhibition (GTI) in regions of brain that regulate sleep (thalamus) and regions that are susceptible to seizures (hippocampus) in Sprague-Dawley rats using a controlled cortical impact model of TBI. The study is designed to test whether reduced GTI (in thalamus and hippocampus) leads to network hyperexcitability, sleep disruptions, and eventual pathogenesis of seizures. Then we will use drugs that potentiate GTI chronically to determine whether GTI can be "rescued" to reduce network excitability, restore sleep disruptions, and prevent seizures. The experimental plan will be to implant EEG electrodes in Sprague-Dawley rats after controlled cortical impact or sham injury, and record for sleep-wake patterns and seizures at 1 week and 3 months after injury for 5 days each time. At the end of the EEG recordings, animals will be sacrificed to obtain slices of thalamus and hippocampus as to run electrophysiological experiments to study GTI and network excitability. Finally, we will measure whether the expression of GABAA receptor subunits that regulate GTI is reduced. In Aim 2, the same experiments will then be repeated following administration of a drug potentiates GTI (gaboxadol) or a drug that improves sleep acting through another (non-GABAergic) mechanism. Data will be analyzed using specific statistical tests (2x3 full factorial analysis with multivariate regression) to understand the interactions of GTI, network excitability, sleep, and seizures following TBI. First, the study can not only shed some light on a specific mechanism through which TBI causes post-traumatic seizures or sleep disruptions but also potentially lay a path for therapeutic measures that can be applied to military personnel and civilians alike. Second, the study could potentially validate the model we chose such that it can be applied for future studies. Currently there are no therapies that have come from bench research to the clinic in treating patients with TBI. Findings of this study could be applied in the future to also study whether post-traumatic stress disorder can be prevented by targeting similar mechanisms.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710049
Entities
People
- Rama Maganti
Organizations
- United States Army
- University of Wisconsin–Madison