Role of TLR4-Driven MMP-9 Activity in Functional Deficits and Epileptogenesis in Hippocampal Dentate Gyrus Following Traumatic Brain Injury
Abstract
Background: Post-traumatic epilepsy (PTE) is a major long-term health challenge following traumatic brain injury (TBI). Despite the wide use of anti-epileptic drugs for early prophylaxis, long-term control of PTE has been notoriously unsuccessful. In addition, our inability to accurately identify individuals at the risk of developing PTE following TBI highlights the urgent need to improve our understanding of the underlying mechanisms. TBI affects the brain in two phases, an acute phase that conjures damages due to sheer mechanical forces and a secondary phase often ranging from days, weeks to months or even years after injury, characterized by an early immune response, inflammation, neuronal death, and extensive morphological alterations. The rationale for this study stems from our previous work examining the neuro-immune axis and from studies demonstrating regulators of synaptic remodeling as an effective target to prevent development of PTE. This proposal will be critical in establishing a bridge in our understanding of how these chain of events are triggered following trauma leading to debilitating short- and long-term consequences. Scientific Objective: The primary objective of this study is to identify a novel immune-molecular-neuronal interaction and its contribution in the development of PTE. The study will also directly the test the therapeutic potential of this interaction as a target for effective pharmacological intervention to prevent PTE and associated cognitive comorbidities. Research Innovation and Impact: This study will be the first to examine a novel interaction between a key regulator of synaptic remodeling believed to contribute to learning, and how immune signaling can alter its function following brain trauma. We propose to systematically investigate this interaction at a molecular, neuronal, circuit, and behavioral level using a rodent model of TBI known to result in development of epilepsy and commonly used for preclinical evaluation of drug therapies. In Aim 1, the study will establish a link between the immune signal and downstream molecular pathway using complementary genetic and translationally relevant pharmacological approaches, followed by examination of the effect of this signaling on neuronal structure and physiology enabling a holistic molecular to cellular cause and effect analysis. PTE often develops following a latent period that may extend from a few months to 30-35 years post-injury. This delay in development of epilepsy also provides a unique window to study, predict, and deploy effective therapies to mitigate long-term effects. Aim 2 of this study is designed to capitalize on this “latent period” by identifying early changes in a specific electrical signals in the brain as a marker for subsequent development of PTE. Moreover, Aim 2 will evaluate deficits in spatial learning, both as a behavioral readout and as a measure of concerted interactions between high-level brain regions involved in memory. Fundamental insight from these experiments will provide much-needed tools to track risk for subsequent seizures or memory impairments and advance our understanding of the role of neuro-immune mechanisms in learning. The ultimate goal of this study is to test the therapeutic efficacy of targeting this immunemolecular-neuronal axis in preventing PTE. To this end, the final studies in Aim 2 will directly test the effect of early pharmacological intervention in mitigating the development of PTE and associated cognitive impairments. Military Benefit: Despite the improvements in post-traumatic medical care, studies found the incidence of developing PTE unaltered following World War I, World War II, the Korean conflict, and the Vietnam War. Long-term studies found 22%-43% of war Veterans develop PTE within 5 years, which increased to a staggering 50% at 10 years. Factoring in the recent estimates on military TBI showing a significant increase in injuries between 2009-2016, the burden of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110684
Entities
People
- Deepak Subramanian
Organizations
- United States Army
- University of California, Riverside