Neurological disorders such as epilepsy and memory loss that develop several years after traumatic brain injury are a major source of physical disability and economic burden after brain trauma. The time window between the initial insult and the disease suggest that progressive changes that occur after brain injury underlie neurological disease and that early interventions might prevent these debilitating outcomes. The hippocampal dentate gyrus is the major focus of neuronal damage and increased excitability after concussive brain injury and in post-traumatic temporal lobe epilepsy. Apart from injuring neurons, traumatic release of endogenous molecules from disrupted cells and extracellular matrix can activate pattern-recognition receptors of the innate immune system including Toll-like receptors. Certain TLR subtypes, including TLR4 are expressed in neurons and regulate neurogenesis and cell death. The central hypothesis of this proposal is that, early post-injury increase in activation of neuronal TLR4 alters excitability and leads to excitotoxic damage of specific dentate neuronal types and facilitating acute and chronic increases in network excitability. Using the rodent fluid percussion injury model of concussive brain trauma and current physiological techniques, Aim 1 will distinguish the cellular, signaling and channel mechanisms underlying TLR4 modulation of neuronal excitability in the normal brain and early after brain injury.
Aim 2 will determine whether TLR4 activation in specific interneuronal populations contributes to excitotoxic injury and loss of certain interneuronal subtypes. Finally, Aim 3 will use a combination of histological, physiological and behavioral assays to test whether selective TLR4 antagonists reduce long-term susceptibility to epilepsy and memory deficits after brain injury. It is anticipated that the proposed studies will identify novel roles for perturbed TLR4 signaling in post-traumatic pathology and generate strategies for targeted treatment to improve the long-term neurological outcome after traumatic brain injury while preserving normal physiology. Such preventive strategies will greatly improve the quality of life of patients after brain injury and, in keeping with the NINDS mission, decrease the burden that post-traumatic neurological diseases place on the health care system.

Public Health Relevance

Over 1.7 million US civilians and an increasing number of combat veterans suffer from brain injuries and associated complications including epilepsy and memory loss. Experiments proposed herein will identify mechanisms by which innate immune response contributes to long-term neurological complications of brain injury and distinguish mechanisms of normal from pathological signaling. The mechanistic understanding from this study will enable targeting specific signaling pathways to prevent post-injury neurological dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Schools of Medicine
United States
Zip Code
Chitturi, Jyothsna; Li, Ying; Santhakumar, Vijayalakshmi et al. (2018) Early behavioral and metabolomic change after mild to moderate traumatic brain injury in the developing brain. Neurochem Int 120:75-86
Parent, Maxime; Li, Ying; Santhakumar, Vijayalakshmi et al. (2018) Alterations of Parenchymal Microstructure, Neuronal Connectivity, and Cerebrovascular Resistance at Adolescence after Mild-to-Moderate Traumatic Brain Injury in Early Development. J Neurotrauma :
Neuberger, Eric J; Gupta, Akshay; Subramanian, Deepak et al. (2017) Converging early responses to brain injury pave the road to epileptogenesis. J Neurosci Res :
Neuberger, Eric J; Swietek, Bogumila; Corrubia, Lucas et al. (2017) Enhanced Dentate Neurogenesis after Brain Injury Undermines Long-Term Neurogenic Potential and Promotes Seizure Susceptibility. Stem Cell Reports 9:972-984
Subramanian, Deepak; Santhakumar, Viji (2017) Lighting the Fuse: Deconstructing Complex Network Interactions Using On-Demand Seizures. Epilepsy Curr 17:174-176
Swietek, Bogumila; Gupta, Akshay; Proddutur, Archana et al. (2016) Immunostaining of Biocytin-filled and Processed Sections for Neurochemical Markers. J Vis Exp :