Signaling mediated by the neurotrophin receptor, TrkB, has been implicated in diverse psychiatric and neurological disorders. Notably, TrkB is activated during and is required for limbic epileptogenesis. During the current funding period, we discovered a downstream signaling pathway by which TrkB activation promotes limbic epileptogenesis in the kindling model in vivo, namely the PLC31 pathway. In vitro studies demonstrate that TrkB-mediated PLC31 signaling promotes reduced expression of the K-Cl co-transporter, KCC2, resulting in accumulation of intracellular chloride ([Cl-]i), a shift of EGABA in a depolarizing direction, and potentially impaired synaptic inhibition. Direct study of human epileptic tissue advances reduced expression of KCC2 and the resulting accumulation of [Cl-]i as an important mechanism contributing to the hyperexcitability of limbic epilepsy. These findings underscore the importance of elucidating the signaling pathways operative in animal models in vivo that reduce KCC2 expression. We hypothesize that TrkB- mediated activation of PLC31 mediates the reduced KCC2 expression in limbic epileptogenesis in vivo and promotes limbic epileptogenesis. We will test these hypotheses with biochemical, immunohistochemical, electrophysiological, and imaging methods focused on wild type (WT) and genetically modified mice in vivo and ex vivo. Insight into the signaling pathways downstream from TrkB that promote limbic epileptogenesis promises to facilitate development of specific and novel therapies while simultaneously shedding light on the underlying cellular mechanisms.

Public Health Relevance

Limbic epilepsy is a common and frequently devastating neurological disorder. Successful completion of this project will provide information useful for the development of novel therapeutics aimed at preventing the development and/or progression of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056217-07
Application #
8303260
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2006-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$334,425
Indirect Cost
$120,050
Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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 Cγ1 Prevents Epilepsy Induced by Status Epilepticus. Neuron 88:484-91
Liu, Gumei; Kotloski, Robert J; McNamara, James O (2014) Antiseizure effects of TrkB kinase inhibition. Epilepsia 55:1264-73
Harward, Stephen C; McNamara, James O (2014) Aligning animal models with clinical epilepsy: where to begin? Adv Exp Med Biol 813:243-51
He, Xiao Ping; Wen, Renren; McNamara, James O (2014) Impairment of kindling development in phospholipase Cγ1 heterozygous mice. Epilepsia 55:456-63
Helgager, Jeffrey; Liu, Gumei; McNamara, James O (2013) The cellular and synaptic location of activated TrkB in mouse hippocampus during limbic epileptogenesis. J Comp Neurol 521:499-521, Spc1
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
Liu, Gumei; Gu, Bin; He, Xiao-Ping et al. (2013) Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. Neuron 79:31-8
Singh, Shatrunjai P; He, Xiaoping; McNamara, James O et al. (2013) Morphological changes among hippocampal dentate granule cells exposed to early kindling-epileptogenesis. Hippocampus 23:1309-20
Harward, Stephen C; McNamara, James O (2013) In search of the ever-elusive positive endozepine. Neuron 78:951-2

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