In the United States, traumatic brain injury (TBI) occurs every 21 seconds, afflicts up to two million people annually, and is the primary cause of death and disability in young adults and children. The initial TBI lesion is now known to propagate long-lasting secondary heterogeneous pathologies, which underlie long term morbidities. The hippocampus, a brain structure crucial for learning and memory and also a frequent site of seizure initiation, is often damaged during TBI. It is still unknown however, how injury-induced changes in cellular metabolism, neurotransmitter function, and synaptic plasticity lead to the altered regional hippocampal excitability that contributes to post traumatic cognitive impairment and seizures. Our laboratory has elucidated novel connections between metabolic and electrophysiological alterations in the injured hippocampus. We have previously established that diminshed inhibitory efficacy compromises dentate gyrus function. Moreover, we have identified several molecular and metabolic adaptations in hippocampal function that may underlie reduced dentate gyrus filtering efficiency of afferent input and suppression of hippocampal long-term potentiation, including reduced expression of the chloride transporter KCC2, reduced NMDA receptor mediated calcium influx, and disruption of essential amino acid metabolism. Our long-range goal is to develop effective and well-tolerated strategies for ameliorating pathologies associated with TBI. The objective of this application is to understand the causes and consequences of injury-induced alterations in hippocampal excitability and metabolism. Our preliminary data led to the formulation of the following CENTRAL HYPOTHESIS: TBI-induced alteration in neuronal amino acid metabolism causes regional changes in hippocampal excitability, which together with disruptions in chloride transport and calcium mediated signaling, results in increased susceptibility to seizures and cognitive deficit. To test this hypothesis, a multi-disciplinary approach focused on elucidating basic mechanisms will examine excitatory and inhibitory function, as well as neuronal metabolism in hippocampal subregions. A thorough comprehension of these mechanisms will provide insight for directing the development of potential therapies to ameliorate cognitive dysfunction and seizures in TBI patients.

Public Health Relevance

Traumatic brain injury (TBI) is a major public health issue, which has a significant impact upon our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to develop effective and well-tolerated clinical management strategies for reducing or ameliorating cognitive dysfunction and seizures in TBI patients.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Michel, Mary E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital of Philadelphia
United States
Zip Code
Bourgeois, Elliot B; Johnson, Brian N; McCoy, Almedia J et al. (2014) A toolbox for spatiotemporal analysis of voltage-sensitive dye imaging data in brain slices. PLoS One 9:e108686
Xiong, Guoxiang; Elkind, Jaclynn A; Kundu, Suhali et al. (2014) Traumatic brain injury-induced ependymal ciliary loss decreases cerebral spinal fluid flow. J Neurotrauma 31:1396-404
Lim, Miranda M; Elkind, Jaclynn; Xiong, Guoxiang et al. (2013) Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. Sci Transl Med 5:215ra173
Burd, Irina; Bentz, Amy I; Chai, Jinghua et al. (2010) Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain. J Neurosci Res 88:1872-81
Cole, Jeffrey T; Mitala, Christina M; Kundu, Suhali et al. (2010) Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci U S A 107:366-71
Bevers, Matthew B; Ingleton, Lori P; Che, Dongfang et al. (2010) RNAi targeting micro-calpain increases neuron survival and preserves hippocampal function after global brain ischemia. Exp Neurol 224:170-7
Royo, N C; LeBold, D; Magge, S N et al. (2007) Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function. Neuroscience 148:359-70
Cohen, Akiva S; Pfister, Bryan J; Schwarzbach, Elizabeth et al. (2007) Injury-induced alterations in CNS electrophysiology. Prog Brain Res 161:143-69