title: Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis.
abstract: 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.
authors.affiliation: Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Xiao Ping
authors.initials: XP
authors.lastname: He
authors.forename: Enhui
authors.initials: E
authors.lastname: Pan
authors.forename: Carla
authors.initials: C
authors.lastname: Sciarretta
authors.forename: Liliana
authors.initials: L
authors.lastname: Minichiello
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D007696:Kindling, Neurologic / Q000235:genetics; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051966:Phospholipase C gamma / Q000096:biosynthesis / Q000502:physiology*; D010862:Pilocarpine; D020813:Receptor, trkB / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000378:metabolism
chemical_list: D010862:Pilocarpine; D020813:Receptor, trkB; D051966:Phospholipase C gamma
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