Epilepsy arising months or years after a head injury is a common and often devastating complication, accounting for at least 10,000 new cases of post-traumatic epilepsy annually in the U.S. alone. Although anti- convulsants are commonly prescribed for anti-epileptogenic purposes, no clinically effective anti-epileptogenic agents have been identified. Understanding the molecular basis of epileptogenesis could lead to a pharmacology aimed at prevention of epilepsy. Insight into the mechanisms underlying development of kindling may unravel part of the molecular basis of epileptogenesis. Two necessary conditions have been identified for the development of kindling: the periodic elicitation of brief electrical seizures (afterdischarges [ADs]) and activation of the NMDA receptor during the AD. How fleeting activation of glutamate receptors during AD produces the lifelong hyperexcitability of kindling is unclear. The unifying hypothesis of this application proposes that glutamate receptor activation during stimulation-evoked afterdischarge triggers a signaling cascade which culminates in expression of immediate early genes (IEG) and target genes including neurotrophins and their receptors, thereby inducing structural modifications of neurons in multiple sites, and that these structural modifications contribute to kindling development The objective of this proposal is to test several aspects of this unifying hypothesis, focusing on the dentate granule cells as a model in which to probe the relationship between glutamate receptor regulation of gene expression, structural neuronal modifications, and kindling development. We have established primary cultures of dentate gyrus neurons from post-natal rats and will test aspects of this hypothesis in parallel investigations in vitro and in the kindling model in vivo. This hypothesis will be tested with 3 specific aims: 1. To investigate part of the signaling pathways by which the Ca++ influx signals triggered by glutamate receptor activation regulate lEG expression in dentate gyrus and cortical neurons in vitro. 2. To examine the morphoregulatory and neuroprotective effects of the neurotrophins on dentate gyrus neurons. 3. To determine whether genetic and pharmacologic interventions at various sites in the signaling cascade modify molecular (lEG and neurotrophin gene expression), structural (axonal sprouting of granule cells), and functional (kindling development) events in vivo. Identification of pharmacologic interventions that inhibit kindling development may provide novel therapies for prophylaxis of post-traumatic epilepsy. Fundamental insights emerging from this work may also shed light on signal transduction in a diversity of physiologic and pathologic settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032334-07
Application #
6151562
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Fureman, Brandy E
Project Start
1994-02-01
Project End
2001-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
7
Fiscal Year
2000
Total Cost
$304,062
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Danzer, Steve C; McNamara, James O (2004) Localization of brain-derived neurotrophic factor to distinct terminals of mossy fiber axons implies regulation of both excitation and feedforward inhibition of CA3 pyramidal cells. J Neurosci 24:11346-55
Danzer, Steve C; He, Xiaoping; McNamara, James O (2004) Ontogeny of seizure-induced increases in BDNF immunoreactivity and TrkB receptor activation in rat hippocampus. Hippocampus 14:345-55
Bausch, Suzanne B; McNamara, James O (2004) Contributions of mossy fiber and CA1 pyramidal cell sprouting to dentate granule cell hyperexcitability in kainic acid-treated hippocampal slice cultures. J Neurophysiol 92:3582-95
Danzer, S C; Pan, E; Nef, S et al. (2004) Altered regulation of brain-derived neurotrophic factor protein in hippocampus following slice preparation. Neuroscience 126:859-69
Barnes, Gregory; Puranam, Ram S; Luo, Yuling et al. (2003) Temporal specific patterns of semaphorin gene expression in rat brain after kainic acid-induced status epilepticus. Hippocampus 13:1-20
Danzer, Steve C; Crooks, Kristy R C; Lo, Donald C et al. (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754-63
Bausch, S B; McNamara, J O (2000) Synaptic connections from multiple subfields contribute to granule cell hyperexcitability in hippocampal slice cultures. J Neurophysiol 84:2918-32
Routbort, M J; Bausch, S B; McNamara, J O (1999) Seizures, cell death, and mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures. Neuroscience 94:755-65
Bausch, S B; McNamara, J O (1999) Experimental partial epileptogenesis. Curr Opin Neurol 12:203-9

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