Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis

The BDNF receptor, TrkB, is critical to limbic epileptogenesis, but the responsible downstream signaling pathways are unknown. We hypothesized that TrkB-dependent activation of phospholipase Cgamma1 (PLCgamma1) signaling is the key pathway and tested this in trkB(PLC/PLC) mice carrying a mutation (Y...

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Bibliographic Details
Published in:The Journal of neuroscience 2010-05, Vol.30 (18), p.6188
Main Authors: He, Xiao Ping, Pan, Enhui, Sciarretta, Carla, Minichiello, Liliana, McNamara, James O
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Epilepsy - chemically induced
Epilepsy - genetics
Epilepsy - physiopathology
Hippocampus - metabolism
Hippocampus - physiology
Kindling, Neurologic - genetics
Long-Term Potentiation - genetics
Long-Term Potentiation - physiology
Mice
Mice, Transgenic
Mutation
Phospholipase C gamma - biosynthesis
Phospholipase C gamma - physiology
Pilocarpine
Receptor, trkB - biosynthesis
Receptor, trkB - genetics
Receptor, trkB - physiology
Signal Transduction - genetics
Signal Transduction - physiology
Synapses - metabolism
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Summary:The BDNF receptor, TrkB, is critical to limbic epileptogenesis, but the responsible downstream signaling pathways are unknown. We hypothesized that TrkB-dependent activation of phospholipase Cgamma1 (PLCgamma1) signaling is the key pathway and tested this in trkB(PLC/PLC) mice carrying a mutation (Y816F) that uncouples TrkB from PLCgamma1. Biochemical measures revealed activation of both TrkB and PLCgamma1 in hippocampi in the pilocarpine and kindling models in wild-type mice. PLCgamma1 activation was decreased in hippocampi isolated from trkB(PLC/PLC) compared with control mice. Epileptogenesis assessed by development of kindling was inhibited in trkB(PLC/PLC) compared with control mice. Long-term potentiation of the mossy fiber-CA3 pyramid synapse was impaired in slices of trkB(PLC/PLC) mice. We conclude that TrkB-dependent activation of PLCgamma1 signaling is an important molecular mechanism of limbic epileptogenesis. Elucidating signaling pathways activated by a cell membrane receptor in animal models of CNS disorders promises to reveal novel targets for specific and effective therapeutic intervention.
ISSN:1529-2401
DOI:10.1523/JNEUROSCI.5821-09.2010