Each year an estimated 1.5 million people sustain traumatic brain injury, presenting an enormous social and medical problem, with an economic burden exceeding $50 billion annually in the US. Head injury is one of the most important causes of acquired epilepsy;however, the mechanisms underlying post-traumatic epilepsy are not understood. Recently, we discovered that the GABAergic control of hippocampal pyramidal cells is subnetwork-specific (differential GABAergic inhibition exists for distinct pyramidal cell subpopulations) and temporally ordered (different interneuron subtypes fire in a particular temporal sequence during behaviorally relevant network oscillations). Here we propose to test the hypothesis that there is a significant disruption of the specialized, local GABAergic control o long-distance projecting excitatory pyramidal cells in post-traumatic epilepsy and that this compromised GABAergic inhibition constitutes a key mechanism underlying hyperexcitability and spontaneous seizures. The hypothesis will be tested in the controlled cortical impact model of traumatic brain injury during the chronic epilepsy phase, and the assessment will be carried out in the CA1 region of the mouse hippocampus with advanced in vitro and in vivo electrophysiological, immunocytochemical and optogenetic methods, complemented by data-driven, large-scale computational modeling approaches. The experiments of this proposal are designed to specifically target cellular-synaptic mechanisms underlying post-traumatic epilepsy and to test novel closed-loop optogenetic methods to stop chronic seizures in the post-traumatic brain. It is anticipated that defining the functional consequences of experimental post-traumatic epilepsy will aid in the future development of novel treatment strategies.

Public Health Relevance

Many patients who suffered severe traumatic brain injury have repeated spontaneous seizures (epilepsy) that cannot be controlled with existing drug therapies. Spontaneous seizures may be caused by persistently compromised inhibitory circuits that emerge after precipitating insult. The project will determine whether aberrant inhibitory regulation of the hippocampal circuits contributes to the generation of chronic post-traumatic seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS035915-16
Application #
8540796
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (03))
Program Officer
Fureman, Brandy E
Project Start
1997-06-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
16
Fiscal Year
2013
Total Cost
$336,510
Indirect Cost
$117,760
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Bezaire, Marianne J; Soltesz, Ivan (2013) Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity. Hippocampus 23:751-85
Olah, Szabolcs; Fule, Miklos; Komlosi, Gergely et al. (2009) Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 461:1278-81
Echegoyen, Julio; Armstrong, Caren; Morgan, Robert J et al. (2009) Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model. Epilepsy Res 85:123-7