Temporal lobe epilepsy is the most common epileptic syndrome in adults, and also the most intractable. It is considered to be a symptomatic condition, i.e. one associated with a prior insult. For the most part, the mechanisms mediating the pathological alterations causing epilepsy remain to be elucidated. The present proposal wilt explore synaptic circuit, cellular and molecular alterations in the hippocampal dentate gyrus, and assess the effects of these alterations on seizure frequency and severity in intact, epileptic animals. Studies are designed to specifically test our CENTRAL HYPOTHESIS: Cellular and circuit alterations evident in the epileptic dentate gyrus combine to generate a tonic imbalance in function, which compromises the normal 'gatekeeper' function of this region, and results in a hippocampus which is predisposed to generate seizures. To test this hypothesis, the cellular and circuit properties of the dentate gyrus are to be studied in tissue isolated from epileptic animals, and pharmacological and transgenic interventions are to be explored in intact animals, examining effects on seizure frequency and severity. Research directed at testing our central hypothesis will focus on 3 SPECIFIC AIMS:
AIM 1 : Determine the role played by zinc released from sprouted mossy fiber terminals in dentate gyrus circuit hyperexcitability in epileptic animals.
AIM 2 : Determine the role played by birth of large numbers of new dentate granule cells triggered by the development of epilepsy in the subsequent emergence of dentate gyrus circuit hyperexcitability characteristic of chronic temporal lobe epilepsy AIM 3. Determine the effects of zinc released from sprouted mossy fiber recurrent collaterals and of the birth of large numbers of new neurons on seizure frequency and severity in epileptic animals. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will attempt to better understand how divergent cellular and circuit alterations may interact to predispose the hippocampus to seizure generation in temporal lobe epilepsy. Understanding the nature of epileptogenic changes at the functional, molecular, and whole animal level is necessary to achieve to facilitate the development of new therapeutic strategies to better treat and perhaps cure this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS032403-12
Application #
6780930
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Fureman, Brandy E
Project Start
1994-07-01
Project End
2006-05-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
12
Fiscal Year
2004
Total Cost
$399,500
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Terunuma, Miho; Xu, Jianwei; Vithlani, Mansi et al. (2008) Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. J Neurosci 28:376-84
Carlson, Greg C; Coulter, Douglas A (2008) In vitro functional imaging in brain slices using fast voltage-sensitive dye imaging combined with whole-cell patch recording. Nat Protoc 3:249-55
Ding, Shinghua; Fellin, Tommaso; Zhu, Yingzi et al. (2007) Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci 27:10674-84
Pathak, Hemal R; Weissinger, Florian; Terunuma, Miho et al. (2007) Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy. J Neurosci 27:14012-22
Liang, Shu-Ling; Carlson, Gregory C; Coulter, Douglas A (2006) Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J Neurosci 26:8537-48
Dong, Yi Na; Wu, Hai-Yan; Hsu, Fu-Chun et al. (2006) Developmental and cell-selective variations in N-methyl-D-aspartate receptor degradation by calpain. J Neurochem 99:206-17
Ang, Chyze W; Carlson, Gregory C; Coulter, Douglas A (2006) Massive and specific dysregulation of direct cortical input to the hippocampus in temporal lobe epilepsy. J Neurosci 26:11850-6
Porter, Brenda E; Zhang, Guojun; Celix, Juanita et al. (2005) Heterogeneous GABAA receptor subunit expression in pediatric epilepsy patients. Neurobiol Dis 18:484-91
Ang, Chyze W; Carlson, Gregory C; Coulter, Douglas A (2005) Hippocampal CA1 circuitry dynamically gates direct cortical inputs preferentially at theta frequencies. J Neurosci 25:9567-80
Zhang, G; Raol, Y H; Hsu, F-C et al. (2004) Effects of status epilepticus on hippocampal GABAA receptors are age-dependent. Neuroscience 125:299-303

Showing the most recent 10 out of 17 publications