Abstract

Traumatic CNS injury causes several neurological disorders that are characterized by a delayed increase in excitability, such as posttraumatic epilepsy, by unknown mechanisms. In this proposal, we focus on two fundamental pre- and postsynaptic consequences of traumatic injury that may account for hyperexcitability in these conditions: axonal injury and denervation of neuronal populations. The Hypotheses: Neuronal excitability is increased after a penetrating injury because 1) the release of neurotrophins triggers presynaptic axonal sprouting, and 2) degeneration of severed axons triggers an increase in the intrinsic postsynaptic excitability of partially denervated cells. If so, then preventing axonal sprouting and restoring postsynaptic excitability will alleviate injury- induced hyperexcitability and provide useful therapeutic approaches for posttraumatic epilepsy. The Model: We will test these hypotheses in a model of penetrating CNS injury in rats and genetically altered mice. Posttraumatic epilepsy will be studied electrophysiologically and morphologically in ex vivo hippocampal slices and in hippocampal slice cultures at various times after making a transection of the Schaffer collateral pathway because axonal injury and neuronal denervation can be spatially confined to the CA3 and CA1 regions, respectively.
AIM 1 : Determine the role of presynaptic axonal sprouting as a cause of injury-induced hyperexcitability in the hippocampus in vitro and in vivo. Mice in which the trkB neurotrophin receptor has been modified to render it sensitive to pharmacological blockade will be used to test the hypothesis that activation of trkB receptors is required for axonal sprouting and hyperexcitability.
AIM 2 : Determine the postsynaptic mechanisms underlying injury-induced hyperexcitability in the hippocampus. We will test the hypotheses that glutamate supersensitivity and increased intrinsic hyperexcitability occur in CA1 pyramidal cells after denervation. The Goal: To better understand the causes of posttraumatic epilepsy and, ultimately, to offer new and improved prophylactic therapeutic strategies to cure or prevent these conditions. Project Narrative: We seek to discover the causes of the form of epilepsy that occurs after a severe head injury and to develop new therapies to treat or prevent this condition.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040338-07
Application #
7738947
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
2000-07-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
7
Fiscal Year
2010
Total Cost
Indirect Cost

  Institution

Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201

  Publications

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, Céline; 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
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
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
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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