The overall goal of this proposal is to begin the investigation of the mechanisms responsible for the genesis and progression of posttraumatic epilepsy (PTE) induced by fluid percussion injury (FPI), a relevant model of concussive closed head injury in the rat.In our most recent work we 1) discovered and characterized different types of chronic spontaneous recurrent partial seizures (CSRPSs grade 1, 2 and 3) following rostral parasaggital FPI (rpFPI) in the rat;2) discovered that rpFPI-induced PTE is a progressive disorder that results, months after injury, in mesial-temporal lobe epilepsy (MTLE) with dual pathology. The present proposal will focus on defining the neural substrates of rpFPI-induced CSRPSs, on the mechanisms of heterogeneity of FPI-induced CSRPSs, and on their mechanisms of genesis and progression.
Specific Aims : to test the following hypotheses: 1) that the frontal-parietal neocortex at the site of rpFPI develops into the early epileptic focus, responsible for grade 1 and 2 seizures, while hippocampus and piriform cortex develop epileptic foci, responsible for grade 3 seizures, at later times. 2) that the probability of developing PTE following FPI,as well as seizure type, frequency and duration, their underlying pathology, and their temporal progression, depends on the degree and location of the injury. 3) that neuronal and synaptic activity within the incipient early epileptic focus is required for posttraumatic epileptogenesis to occur. 4) that a kindling-like cellular phenomenon mediated by the early epileptic focus is responsible for hippocampal epileptogenesis. 5) that the pharmacological responsiveness of FPI-induced epilepsy changes with time, as the disease progresses, as a function of seizure type and temporal lobe sclerosis. In addition, we aim to develop a murine model of FPI-induced PTE to introduce the use of genetically engineered mice in the investigation of risk factors and basic mechanisms ofPTE. Because of the unparalleled phenotypic and etiological similarities existing between this rodent model and human PTE the data collected will lead to the elucidation of more relevant mechanisms of genesis and progression of PTE, and to a better standardization of the model to the advantage of both basic and translational research efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053928-04
Application #
7577378
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
2006-06-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$340,821
Indirect Cost
Name
University of Washington
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
D'Ambrosio, Raimondo; Eastman, Clifford L; Darvas, Felix et al. (2013) Mild passive focal cooling prevents epileptic seizures after head injury in rats. Ann Neurol 73:199-209
Eastman, Clifford L; Verley, Derek R; Fender, Jason S et al. (2011) Antiepileptic and antiepileptogenic performance of carisbamate after head injury in the rat: blind and randomized studies. J Pharmacol Exp Ther 336:779-90
Curia, Giulia; Levitt, Michael; Fender, Jason S et al. (2011) Impact of injury location and severity on posttraumatic epilepsy in the rat: role of frontal neocortex. Cereb Cortex 21:1574-92
D'Ambrosio, Raimondo; Miller, John W (2010) What is an epileptic seizure? Unifying definitions in clinical practice and animal research to develop novel treatments. Epilepsy Curr 10:61-6
Eastman, Clifford L; Verley, Derek R; Fender, Jason S et al. (2010) ECoG studies of valproate, carbamazepine and halothane in frontal-lobe epilepsy induced by head injury in the rat. Exp Neurol 224:369-88
Stewart, Tessandra H; Eastman, Clifford L; Groblewski, Peter A et al. (2010) Chronic dysfunction of astrocytic inwardly rectifying K+ channels specific to the neocortical epileptic focus after fluid percussion injury in the rat. J Neurophysiol 104:3345-60
D'Ambrosio, Raimondo; Hakimian, Shahin; Stewart, Tessandra et al. (2009) Functional definition of seizure provides new insight into post-traumatic epileptogenesis. Brain 132:2805-21
Jung, Sangwook; Jones, Terrance D; Lugo Jr, Joaquin N et al. (2007) Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy. J Neurosci 27:13012-21