Understanding partial epileptogenesis in cellular and molecular terms may provide clues for developing effective preventive therapies. Our preliminary studies reveal that a specific subtype of neurotrophin receptor, TrkB, is required for epileptogenesis in the kindling model. The objectives of this proposal are to begin to explore the mechanisms by which absence of TrkB limits epileptogenesis and to further evaluate TrkB as a potential target for anti-epileptogenic therapies. These objectives will be accomplished by study of genetically modified mice with biochemical, anatomic, and electrophysiological methods. We propose four Aims. To examine the dendritic structure and synaptic physiology of dentate granule cells in TrkB -/- and WT mice. To examine the development of amygdala kindling in mice in which TrkB signaling is inhibited de novo in the postnatal brain. To examine the effect of inhibition of TrkB signaling on persistence of hyperexcitability in the kindling model. To examine the effects of inhibiting TrkB signaling on limbic epileptogenesis and mossy fiber sprouting of the granule cells in multiple models. Successful completion of these Specific Aims could establish TrkB and its signaling pathways as highly attractive molecular targets for development of pharmacologic agents for prevention of epilepsy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056217-03
Application #
7460822
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Stewart, Randall R
Project Start
2006-07-15
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$375,024
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
Dingledine, Raymond; Coulter, Douglas A; Fritsch, Brita et al. (2017) Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data 4:170061
Hedrick, Nathan G; Harward, Stephen C; Hall, Charles E et al. (2016) Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity. Nature 538:104-108
Harward, Stephen C; Hedrick, Nathan G; Hall, Charles E et al. (2016) Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature 538:99-103
Puranam, Ram S; He, Xiao Ping; Yao, Lijun et al. (2015) Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus. J Neurosci 35:8866-81
Gu, Bin; Huang, Yang Zhong; He, Xiao-Ping et al. (2015) A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase C?1 Prevents Epilepsy Induced by Status Epilepticus. Neuron 88:484-91
Harward, Stephen C; McNamara, James O (2014) Aligning animal models with clinical epilepsy: where to begin? Adv Exp Med Biol 813:243-51
Liu, Gumei; Kotloski, Robert J; McNamara, James O (2014) Antiseizure effects of TrkB kinase inhibition. Epilepsia 55:1264-73
Helgager, Jeffrey; Huang, Yang Zhong; Mcnamara, James O (2014) Brain-derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo. J Comp Neurol 522:3885-99
He, Xiao Ping; Wen, Renren; McNamara, James O (2014) Impairment of kindling development in phospholipase C?1 heterozygous mice. Epilepsia 55:456-63
Wang, Hong-Gang; He, Xiao Ping; Li, Qiang et al. (2013) The auxiliary subunit KChIP2 is an essential regulator of homeostatic excitability. J Biol Chem 288:13258-68

Showing the most recent 10 out of 27 publications