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      A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus

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          SUMMARY

          The BDNF receptor tyrosine kinase, TrkB, underlies nervous system function in both health and disease. Excessive activation of TrkB caused by status epilepticus promotes development of temporal lobe epilepsy (TLE), revealing TrkB as a therapeutic target for prevention of TLE. To circumvent undesirable consequences of global inhibition of TrkB signaling, we implemented a novel strategy aimed at selective inhibition of the TrkB-activated signaling pathway responsible for TLE. Our studies of a mouse model reveal that phospholipase Cγ1 (PLCγ1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCγ1. Treatment with pY816 following status epilepticus inhibited TLE and prevented anxiety-like disorder yet preserved neuroprotective effects of endogenous TrkB signaling. We provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine signaling and identify a therapeutic with promise for prevention of TLE caused by status epilepticus in humans.

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          Author and article information

          Journal
          8809320
          1600
          Neuron
          Neuron
          Neuron
          0896-6273
          1097-4199
          26 September 2015
          17 October 2015
          4 November 2015
          04 November 2016
          : 88
          : 3
          : 484-491
          Affiliations
          [1 ]Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
          [2 ]Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
          [3 ]Department of Electrical and Computer Engineering, Duke University, Durham, NC 27710, USA
          [4 ]Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710, USA
          Author notes
          [* ]Correspondence should be addressed to James O. McNamara, Department of Neurobiology, Duke University Medical Center, Box 3676, Durham, NC 27710, USA. jmc@ 123456neuro.duke.edu
          [5]

          Current Address: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA

          [6]

          Current Address: Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA

          [7]

          Current Address: University System of Georgia MD/PhD Program, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA

          Article
          PMC4636438 PMC4636438 4636438 nihpa725390
          10.1016/j.neuron.2015.09.032
          4636438
          26481038
          1f20049b-f4bf-4a82-886c-669a2f996bc5
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