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 Cγ1 (PLCγ1) signaling is the key pathway and tested this in trkB PLC/PLC mice carrying a mutation (Y816F) that uncouples TrkB from PLCγ1. Biochemical measures revealed activation of both TrkB and PLCγ1 in hippocampi in the pilocarpine and kindling models in wild-type mice. PLCγ1 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 PLCγ1 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.