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). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040276-07
Application #
7263065
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Stewart, Randall R
Project Start
2000-07-05
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
7
Fiscal Year
2007
Total Cost
$274,646
Indirect Cost
Name
Stanford University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Yamawaki, Ruth; Thind, Khushdev; Buckmaster, Paul S (2015) Blockade of excitatory synaptogenesis with proximal dendrites of dentate granule cells following rapamycin treatment in a mouse model of temporal lobe epilepsy. J Comp Neurol 523:281-97
Zhang, Wei; Thamattoor, Ajoy K; LeRoy, Christopher et al. (2015) Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy. Hippocampus 25:594-604
Scharfman, Helen E; Buckmaster, Paul S (2014) Preface. Adv Exp Med Biol 813:xv-xviii
Buckmaster, Paul S (2014) Does mossy fiber sprouting give rise to the epileptic state? Adv Exp Med Biol 813:161-8
Toyoda, Izumi; Bower, Mark R; Leyva, Fernando et al. (2013) Early activation of ventral hippocampus and subiculum during spontaneous seizures in a rat model of temporal lobe epilepsy. J Neurosci 33:11100-15
Heng, Kathleen; Haney, Megan M; Buckmaster, Paul S (2013) High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia 54:1535-41
Colas, D; Chuluun, B; Warrier, D et al. (2013) Short-term treatment with the GABAA receptor antagonist pentylenetetrazole produces a sustained pro-cognitive benefit in a mouse model of Down's syndrome. Br J Pharmacol 169:963-73
Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J et al. (2012) Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 53:571-82
Zhang, Wei; Huguenard, John R; Buckmaster, Paul S (2012) Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy. J Neurosci 32:1183-96
Buckmaster, Paul S; Haney, Megan M (2012) Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy. Epilepsy Res 102:153-9

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