Disruption of TrkB-Mediated Phospholipase C gamma Signaling Inhibits Limbic Epileptogenesis

作者：He Xiao Ping; Pan Enhui; Sciarretta Carla; Minichiello Liliana; McNamara James O^*

来源：Journal of Neuroscience, 2010, 30(18): 6188-6196.

DOI：10.1523/JNEUROSCI.5821-09.2010

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 C gamma 1 (PLC gamma 1) signaling is the key pathway and tested this in trkB(PLC/PLC) mice carrying a mutation (Y816F) that uncouples TrkB from PLC gamma 1. Biochemical measures revealed activation of both TrkB and PLC gamma 1 in hippocampi in the pilocarpine and kindling models in wild-type mice. PLC gamma 1 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 PLC gamma 1 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.

• 出版日期2010-5-5