Enkephalin-mediated hippocampal circuit disinhibition after traumatic brain injury

Portland Va Medical Center, Portland OR

Investigators

Abstract

Background and Innovation: Post-traumatic epilepsy is a potentially devastating consequence of head injury in Veterans that is often resistant to medical treatment. Post-traumatic epilepsy is associated with numerous functional changes in the hippocampus, a region of the brain that is frequently the focal point for the initiation of seizures. Understanding how these rearranged circuit elements contribute to brain hyperexcitability is critical to the development of approaches to improve the treatment of Veterans with epilepsy. One hippocampal circuit alteration noted in epilepsy is dramatic activity-dependent upregulation of the endogenous opioid peptide enkephalin by hippocampal granule cell neurons. Although this phenomenon was originally described in the 1980s, the functional roles of enkephalin-mediated signaling in the hippocampus were not examined at the time due to technical limitations. Our preliminary experiments demonstrate that enkephalin potently blocks inhibitory synaptic function in both the dentate gyrus and region CA3 of the hippocampus. Additionally, our data demonstrate that both neuronal activity and traumatic brain injury (TBI) dramatically upregulate enkephalin expression in the hippocampus. We hypothesize that the activity- dependent increase in enkephalin directly contributes to brain hyperexcitability and post-TBI epilepsy. In this proposal, we will define the impact of activity-associated upregulation of enkephalinergic neurotransmission using translational seizure and TBI modeling in genetically modified mice. Our innovative approach involves electrophysiological and novel opioid biosensor assays to advance our understanding of how activity-dependent enkephalin upregulation affects hippocampal function, and how this contributes to learning deficits and epilepsy after TBI. Additionally, we will use a novel activity-dependent enkephalin gene deletion strategy to facilitate a series of experiments aimed at establishing a translational rationale to reduce seizures and improve outcomes after TBI. Significance and Impact to Veterans Healthcare: Veterans with a history severe TBI have a 50% likelihood of developing post-traumatic epilepsy in the years after their injury, and this is a debilitating, lifelong condition that is difficult to treat. If our work identifies a brain circuit alteration that worsens outcomes after TBI, it will allow for the development of more effective treatments for post-traumatic epilepsy that will have a major benefit on Veterans’ health. As endogenous opioid signaling pathways also control many aspects of behavior beyond the hippocampus, our study is likely to provide additional insights into endogenous opioid signaling that could have implications for increasing our understanding of pain, addiction, and motivated behavior. Path to Translation/Implementation: Our study begins with mechanistic investigations and proceeds through proof-of-concept studies to explicitly determine how the phenomenon of activity-dependent enkephalin upregulation contributes to post- TBI epilepsy. If successful, our next steps will be to develop a more explicit understanding of the molecular pathway sustaining enkephalin expression after TBI, and whether interference with this pathway in mouse models has therapeutic benefit. This will then provide a therapeutic rationale and targetable pathway for the development of treatments for Veterans with post-TBI epilepsy.