PHYSIOLOGY OF STATUS EPILEPTICUS IN VITRO

Summary

Principal Investigator: DOUGLAS COULTER
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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.
Funding Period: 1994-07-01 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Shift of intracellular chloride concentration in ganglion and amacrine cells of developing mouse retina
    Ling Li Zhang
    Deaprtment of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6058, USA
    J Neurophysiol 95:2404-16. 2006
  2. pmc Developmental and cell-selective variations in N-methyl-D-aspartate receptor degradation by calpain
    Yi Na Dong
    Department of Neurology and Pediatrics, University of Pennsylvania and The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 4318, USA
    J Neurochem 99:206-17. 2006
  3. pmc Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1
    Shu Ling Liang
    Division of Neurology and the Pediatric Regional Epilepsy Program, Children s Hospital of Philadelphia, Pennsylvania 19104, USA
    J Neurosci 26:8537-48. 2006
  4. pmc Massive and specific dysregulation of direct cortical input to the hippocampus in temporal lobe epilepsy
    Chyze W Ang
    Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 26:11850-6. 2006
  5. pmc Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpain-mediated NR2B cleavage in neurons and heterologous systems
    Hai Yan Wu
    Departments of Pediatrics and Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Biol Chem 282:20075-87. 2007
  6. pmc Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus
    Shinghua Ding
    Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 27:10674-84. 2007
  7. pmc Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy
    Hemal R Pathak
    Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 27:14012-22. 2007
  8. pmc Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus
    Miho Terunuma
    Department of Neuroscience, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 28:376-84. 2008
  9. pmc In vitro functional imaging in brain slices using fast voltage-sensitive dye imaging combined with whole-cell patch recording
    Greg C Carlson
    Translational Research Laboratory, University of Pennsylvania School of Medicine, Room 2226, 125 S 31st Street, Philadelphia, Pennsylvania 19104 3403, USA
    Nat Protoc 3:249-55. 2008

Detail Information

Publications9

  1. ncbi Shift of intracellular chloride concentration in ganglion and amacrine cells of developing mouse retina
    Ling Li Zhang
    Deaprtment of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6058, USA
    J Neurophysiol 95:2404-16. 2006
    ..Our results support the hypothesis that a shift from high [Cl-]i to low causes GABA to switch from excitatory to inhibitory...
  2. pmc Developmental and cell-selective variations in N-methyl-D-aspartate receptor degradation by calpain
    Yi Na Dong
    Department of Neurology and Pediatrics, University of Pennsylvania and The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 4318, USA
    J Neurochem 99:206-17. 2006
    ..Our data suggest that the susceptibility of the NMDA receptor to cleavage by calpain varies with neuronal maturity in a manner that may alter its electrophysiological properties...
  3. pmc Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1
    Shu Ling Liang
    Division of Neurology and the Pediatric Regional Epilepsy Program, Children s Hospital of Philadelphia, Pennsylvania 19104, USA
    J Neurosci 26:8537-48. 2006
    ..We conclude that the glutamate-glutamine cycle is a major contributor to synaptic GABA release under physiological conditions, which dynamically regulates inhibitory synaptic strength...
  4. pmc Massive and specific dysregulation of direct cortical input to the hippocampus in temporal lobe epilepsy
    Chyze W Ang
    Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 26:11850-6. 2006
    ..This dysregulated temporoammonic pathway is critically positioned to mediate generation and/or propagation of seizure activity in the hippocampus...
  5. pmc Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpain-mediated NR2B cleavage in neurons and heterologous systems
    Hai Yan Wu
    Departments of Pediatrics and Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Biol Chem 282:20075-87. 2007
    ..Thus, the Fyn-controlled regulation of NMDA receptor cleavage by calpain may play critical roles in controlling NMDA receptor properties during synaptic plasticity and excitotoxicity...
  6. pmc Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus
    Shinghua Ding
    Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 27:10674-84. 2007
    ..These observations support neurotoxic roles for astrocytic gliotransmission in pathological conditions and identify this process as a novel therapeutic target...
  7. pmc Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy
    Hemal R Pathak
    Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 27:14012-22. 2007
    ..This pathophysiological process may constitute a significant mechanism linking injury to the subsequent development of epilepsy...
  8. pmc Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus
    Miho Terunuma
    Department of Neuroscience, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 28:376-84. 2008
    ..Thus, enhancing phosphorylation of GABA(A)Rs or selectively blocking their interaction with AP2 may provide novel therapeutic strategies to ameliorate SE...
  9. pmc In vitro functional imaging in brain slices using fast voltage-sensitive dye imaging combined with whole-cell patch recording
    Greg C Carlson
    Translational Research Laboratory, University of Pennsylvania School of Medicine, Room 2226, 125 S 31st Street, Philadelphia, Pennsylvania 19104 3403, USA
    Nat Protoc 3:249-55. 2008
    ..Thus, the combined VSD imaging and whole-cell patch approach provides experimental resolution spanning single-cell electrophysiology to complex local circuit responses...