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.
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.
|Liu, Gumei; Kotloski, Robert J; McNamara, James O (2014) Antiseizure effects of TrkB kinase inhibition. Epilepsia 55:1264-73|
|He, Xiao Ping; Wen, Renren; McNamara, James O (2014) Impairment of kindling development in phospholipase C?1 heterozygous mice. Epilepsia 55:456-63|
|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; 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|
|Harward, Stephen C; McNamara, James O (2013) In search of the ever-elusive positive endozepine. Neuron 78:951-2|
|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|
|Pan, Enhui; Zhang, Xiao-an; Huang, Zhen et al. (2011) Vesicular zinc promotes presynaptic and inhibits postsynaptic long-term potentiation of mossy fiber-CA3 synapse. Neuron 71:1116-26|
|Danzer, Steve C; He, Xiaoping; Loepke, Andreas W et al. (2010) Structural plasticity of dentate granule cell mossy fibers during the development of limbic epilepsy. Hippocampus 20:113-24|
|Huang, Yang Z; McNamara, James O (2010) Mutual regulation of Src family kinases and the neurotrophin receptor TrkB. J Biol Chem 285:8207-17|
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