The Problem: Epilepsy is a common consequence of traumatic head injury. Its cause is unknown. The Hypotheses: 1) The release of neurotrophins after traumatic CNS injury triggers axonal sprouting by pyramidal cells. 2) The glutamate sensitivity and excitability of postsynaptic target cells increase as a consequence of partial denervation. 3) Injury-induced presynaptic axonal sprouting and increased postsynaptic excitability combine synergistically to cause posttraumatic epilepsy. The Model: After Schaffer collateral transection, CA3 cells in hippocampal slice cultures sprout new axon collaterals and CA1 cells become supersensitive to glutamate. These phenomena may account for the lesion-induced hyperexcitability. This model provides an experimentally tractable and informative approach for studying pre- and postsynaptic mechanisms of posttraumatic epilepsy. The genesis of hyperexcitability after axonal injury in this model will therefore be investigated using neuroanatomical, cell biological, and electrophysiological techniques.
AIM 1 : Determine the presynaptic mechanisms underlying injury- induced hyperexcitability. TrkB immunoadhesins, biolistic transfection with full length and dominant negative neurotrophin receptor constructs, and cultures derived from trk receptor knockout mice will be used to test the hypothesis that activation of trk receptors is required for injury-induced axonal sprouting. The hypothesis predicts that lesion-induced sprouting will not occur in the presence of trkB immunoadhesin, in cells transfected with dominant negative irk receptors or in cultures made from trk receptor knock-out mice. Lack of axonal sprouting is predicted to eliminate injury-induced hyperexcitability.
AIM 2 : Determine the postsynaptic mechanisms underlying injury- induced hyperexcitability. Using whole-cell voltage-clamp and laser microphotolysis of caged neurotransmitters targeted to individual distal dendrites, we will test the hypotheses that glutamate supersensitivity and intrinsic hyperexcitability occur in CA1 cells after denervation. The hypothesis predicts that changes in the levels of expression of neurotransmitter receptors and/or changes in intrinsic voltage-dependent ionic conductances underlie the potentiation of dendritic glutamate responses observed previously after Schaffer collateral transection. The Goal: to better understand the causes of posttraumatic epilepsy and, ultimately, to offer new and improved prophylactic therapeutic strategies to cure this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040338-04
Application #
6875711
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
2002-04-01
Project End
2007-12-14
Budget Start
2006-04-01
Budget End
2007-12-14
Support Year
4
Fiscal Year
2005
Total Cost
$282,150
Indirect Cost
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Aungst, Stephanie; England, Pamela M; Thompson, Scott M (2013) Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury. J Neurophysiol 109:813-24
Dinocourt, CĂ©line; Aungst, Stephanie; Yang, Kun et al. (2011) Homeostatic increase in excitability in area CA1 after Schaffer collateral transection in vivo. Epilepsia 52:1656-65
Misonou, Hiroaki; Thompson, Scott M; Cai, Xiang (2008) Dynamic regulation of the Kv2.1 voltage-gated potassium channel during brain ischemia through neuroglial interaction. J Neurosci 28:8529-38
Nestor, Michael W; Mok, Lee-Peng; Tulapurkar, Mohan E et al. (2007) Plasticity of neuron-glial interactions mediated by astrocytic EphARs. J Neurosci 27:12817-28
Debanne, Dominique; Thompson, Scott M; Gahwiler, Beat H (2006) A brief period of epileptiform activity strengthens excitatory synapses in the rat hippocampus in vitro. Epilepsia 47:247-56
Laing, Jennifer M; Gober, Michael D; Golembewski, Erin K et al. (2006) Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice. Mol Ther 13:870-81
Hilton, Genell D; Bambrick, Linda L; Thompson, Scott M et al. (2006) Estradiol modulation of kainic acid-induced calcium elevation in neonatal hippocampal neurons. Endocrinology 147:1246-55
Gober, Michael D; Laing, Jennifer M; Thompson, Scott M et al. (2006) The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures. Brain Res 1119:26-39
Hilton, Genell D; Nunez, Joseph L; Bambrick, Linda et al. (2006) Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol. Eur J Neurosci 24:3008-16
Thompson, Scott M; Kao, Joseph P Y; Kramer, Richard H et al. (2005) Flashy science: controlling neural function with light. J Neurosci 25:10358-65

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