Status epilepticus is characterized by a prolonged, self-sustained seizure that can be resistant to current first line therapies. Although it can occur at any age, status epilepticus is the most common neurological emergency of childhood, especially between the ages of 1 month and 4 years. Fortunately, for some children, status epilepticus occurs without consequence. For others, it is associated with death or long term neurological dysfunction. Because the prognosis is dependent on duration, improved therapies for the treatment of status epilepticus are required. Despite agreement that modifications in GABA-mediated synaptic transmission contribute to the pathogenesis of status epilepticus, our understanding of the cellular mechanisms that underlie this process is not complete;and, many of the prior laboratory studies of the pathogenesis of status epilepticus failed to consider age-dependent mechanisms. Our previous studies focused on alterations in the surface expression and trafficking of the postsynaptic GABAA receptor population during status epilepticus. However, in ongoing studies characterizing chemoconvulsant-induced status epilepticus in animals younger than those used in the prior experiments, we observed a reduction in GABA-mediated inhibition that occurred in the absence of a postsynaptic modification in the GABAA receptor population. These studies suggest a novel central hypothesis that the reduction in the perisomatic inhibition of principal neurons in the hippocampus during status epilepticus in young animals is the result of a presynaptic modification in the release of GABA from basket cells. The proposed research focuses on providing a comprehensive mechanistic description of the changes in GABA-mediated inhibition that occur during status epilepticus at a stage of neurodevelopment at which status epilepticus commonly occurs in humans. We propose to test the predictions of our hypothesis by accomplishing 3 specific aims:
(Aim 1) To demonstrate that the excitability of basket cells is decreased as the result of status epilepticus, (Aim 2) To demonstrate that the mean quantal content of GABA released from basket cells is decreased as the result of status epilepticus, and (Aim 3) To demonstrate that the postsynaptic modifications that occur during status epilepticus are age-dependent. An improved understanding of the factors that contribute to the dysfunction of GABAergic synaptic transmission during status epilepticus will provide a basis on which new rational therapies can be based.

Public Health Relevance

These studies seek to understand the mechanisms underlying status epilepticus, prolonged seizures that predispose children and adults to death and long term neurological problems. Unfortunately, current medications used to treat these prolonged seizures sometimes fail. These studies will seek a new target for developing drugs for the treatment of this common neurological emergency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067439-04
Application #
8316287
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Stewart, Randall R
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$330,138
Indirect Cost
$115,763
Name
University of Virginia
Department
Neurology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Joshi, Suchitra; Rajasekaran, Karthik; Hawk, Kyle M et al. (2018) Status epilepticus: Role for etiology in determining response to benzodiazepines. Ann Neurol 83:830-841
Sun, Hua Yu; Goodkin, Howard P (2016) The pervasive reduction of GABA-mediated synaptic inhibition of principal neurons in the hippocampus during status epilepticus. Epilepsy Res 119:30-3
Joshi, Suchitra; Rajasekaran, Karthik; Hawk, Kyle M et al. (2015) Phosphatase inhibition prevents the activity-dependent trafficking of GABAA receptors during status epilepticus in the young animal. Epilepsia 56:1355-65
DiGruccio, Michael R; Joksimovic, Srdjan; Joksovic, Pavle M et al. (2015) Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development. J Neurosci 35:1481-92
Sánchez Fernández, Iván; Abend, Nicholas S; Agadi, Satish et al. (2014) Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG). Seizure 23:87-97
Donner, Elizabeth J; Goodkin, Howard P (2010) Pediatric epilepsy surgery: looking back while moving forward. Neurology 74:1756-7
Goodkin, Howard P; Quigg, Mark (2010) Toothbrushing EEG artifact recorded from chronically implanted subdural electrodes. Neurology 75:1850
Rajasekaran, Karthik; Zanelli, Santina A; Goodkin, Howard P (2010) Lessons from the laboratory: the pathophysiology, and consequences of status epilepticus. Semin Pediatr Neurol 17:136-43