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. 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
  2. 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
  3. 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
  4. 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

Scientific Experts

Detail Information

Publications4

  1. 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...
  2. 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...
  3. 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...
  4. 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...