Dentate Gyrus Circuitry In Temporal Lobe Epilepsy

Summary

Principal Investigator: PAUL SCOTT BUCKMASTER
Affiliation: Stanford University
Country: USA
Abstract: Temporal lobe epilepsy is the most common form of epilepsy in adults and one of the most difficult types to treat. The broad long-term objective of the proposed project is to help reveal the mechanisms of temporal lobe epilepsy so that more effective treatments and preventative strategies can be developed. Specifically, we propose to develop a treatment that will block injury-induced axon sprouting and test a hypothesis of temporal lobe epileptogenesis. It has been hypothesized that epileptogenic injuries trigger axon reorganization (mossy fiber sprouting), which creates a positive-feedback circuit between dentate granule cells that lowers seizure threshold. To test this hypothesis we will develop a treatment to block mossy fiber sprouting (Specific Aim 1). Rats that have experienced pilocarpine-induced status epilepticus will be surgically implanted with a pump and cannula to focally infuse agents into one hippocampus. Inhibitors of calcineurin, a calcium-activated phosphatase, will be tested. After 28 days of continuous infusion, mossy fiber sprouting will be measured using Timm-staining and design-based stereological methods, and synaptic reorganization will be measured with electron microscopy. Agent-infused hippocampi will be compared to uninfused contralateral hippocampi and vehicle-infused controls. The treatment duration sufficient to block mossy fiber sprouting and the permanence of the block will be determined by varying the duration of infusion or the survival period following infusion, respectively (Specific Aim 2). To test whether mossy fiber sprouting contributes to epileptogenesis the septal and temporal parts of both hippocampi will be treated to maximally suppress mossy fiber sprouting, and then rats will be monitored for spontaneous seizure activity using video-taping and EEG recording (Specific Aim 3).
Funding Period: 2000-07-05 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy
    Kathleen Heng
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    Epilepsia 54:1535-41. 2013
  2. pmc Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, CA 94305, United States
    Epilepsy Res 102:153-9. 2012
  3. pmc Mossy cell dendritic structure quantified and compared with other hippocampal neurons labeled in rats in vivo
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305 5342, U S A
    Epilepsia 53:9-17. 2012
  4. pmc Identification of new epilepsy treatments: issues in preclinical methodology
    Aristea S Galanopoulou
    Laboratory of Developmental Epilepsy, Saul R Korey Department of Neurology, Dominick P Purpura Department of Neuroscience, Montefiore Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, NY, USA
    Epilepsia 53:571-82. 2012
  5. pmc Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 32:1183-96. 2012
  6. pmc Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy
    Khushdev K Thind
    Department of Comparative Medicine, Stanford University, California 94305, USA
    J Comp Neurol 518:647-67. 2010
  7. pmc Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA
    Epilepsia 52:2057-64. 2011
  8. pmc Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA
    J Neurosci 31:2337-47. 2011
  9. pmc Stress coping stimulates hippocampal neurogenesis in adult monkeys
    David M Lyons
    Departments of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 107:14823-7. 2010
  10. pmc Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 29:7846-56. 2009

Scientific Experts

  • PAUL SCOTT BUCKMASTER
  • David Lyons
  • Wei Zhang
  • Khushdev K Thind
  • Izumi Toyoda
  • Kathleen Heng
  • Aristea S Galanopoulou
  • Xiling Wen
  • Elizabeth A Ingram
  • Megan M Haney
  • James Stables
  • Asla Pitkanen
  • Jeffrey L Noebels
  • Wolfgang Loscher
  • Michele Simonato
  • John R Huguenard
  • H Steve White
  • Emilio Perucca
  • Jerome Engel
  • Terence J O'Brien
  • Solomon L Moshe
  • Kevin J Staley
  • Guofeng Zhang
  • Ruth Yamawaki
  • Ibanri Phanwar
  • Charles E Ribak

Detail Information

Publications14

  1. pmc High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy
    Kathleen Heng
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    Epilepsia 54:1535-41. 2013
    ..The present study used high-dose rapamycin to more completely block mossy fiber sprouting and to measure the effect on seizure frequency...
  2. pmc Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, CA 94305, United States
    Epilepsy Res 102:153-9. 2012
    ..Those results are substantially better than that of the total sample in which 31% failed to develop status epilepticus and only 34% developed status epilepticus and survived...
  3. pmc Mossy cell dendritic structure quantified and compared with other hippocampal neurons labeled in rats in vivo
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305 5342, U S A
    Epilepsia 53:9-17. 2012
    ..Therefore, electrotonic properties that depend on soma-dendritic structure are likely to be distinct in mossy cells compared to other neurons...
  4. pmc Identification of new epilepsy treatments: issues in preclinical methodology
    Aristea S Galanopoulou
    Laboratory of Developmental Epilepsy, Saul R Korey Department of Neurology, Dominick P Purpura Department of Neuroscience, Montefiore Einstein Epilepsy Management Center, Albert Einstein College of Medicine, Bronx, NY, USA
    Epilepsia 53:571-82. 2012
    ....
  5. pmc Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 32:1183-96. 2012
    ..The aberrant development of these additional positive-feedback circuits might contribute to epileptogenesis in temporal lobe epilepsy...
  6. pmc Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy
    Khushdev K Thind
    Department of Comparative Medicine, Stanford University, California 94305, USA
    J Comp Neurol 518:647-67. 2010
    ....
  7. pmc Rapamycin suppresses axon sprouting by somatostatin interneurons in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA
    Epilepsia 52:2057-64. 2011
    ..The functional consequences of γ-aminobutyric acid (GABA)ergic synaptic reorganization are unclear. Development of new methods to suppress epilepsy-related interneuron axon sprouting might be useful experimentally...
  8. pmc Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA
    J Neurosci 31:2337-47. 2011
    ..These findings are consistent with the hypotheses that hilar neuron loss and ectopic granule cells might contribute to temporal lobe epileptogenesis...
  9. pmc Stress coping stimulates hippocampal neurogenesis in adult monkeys
    David M Lyons
    Departments of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 107:14823-7. 2010
    ..These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression...
  10. pmc Dysfunction of the dentate basket cell circuit in a rat model of temporal lobe epilepsy
    Wei Zhang
    Department of Comparative Medicine, Stanford University, Stanford, California 94305 5342, USA
    J Neurosci 29:7846-56. 2009
    ..These findings suggest dysfunction of the dentate basket cell circuit could contribute to hyperexcitability and seizures...
  11. pmc Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy
    Paul S Buckmaster
    Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA
    J Neurosci 29:8259-69. 2009
    ..However, suppression required continual treatment, and rapamycin treatment did not reverse already established axon reorganization...
  12. pmc Prolonged infusion of inhibitors of calcineurin or L-type calcium channels does not block mossy fiber sprouting in a model of temporal lobe epilepsy
    Elizabeth A Ingram
    Department of Comparative Medicine, Stanford University, Stanford, California, USA
    Epilepsia 50:56-64. 2009
    ..Previous studies have provided encouraging evidence that blocking L-type calcium channels or inhibiting calcineurin during epileptogenic treatments suppresses mossy fiber sprouting...
  13. pmc Synaptic input to dentate granule cell basal dendrites in a rat model of temporal lobe epilepsy
    Khushdev K Thind
    Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA
    J Comp Neurol 509:190-202. 2008
    ..These findings reveal that basal dendrites are a novel source of inhibitory input, but they primarily receive excitatory synapses...
  14. ncbi Prolonged infusion of cycloheximide does not block mossy fiber sprouting in a model of temporal lobe epilepsy
    Izumi Toyoda
    School of Veterinary Medicine, University of California Davis, Davis, CA, U S A
    Epilepsia 46:1017-20. 2005
    ..Conflicting reports exist on whether a single dose of the protein synthesis-blocker cycloheximide administered around the time of an epileptogenic injury can block the eventual development of mossy fiber sprouting...