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

dc.contributor.author

Gu, Bin

dc.contributor.author

Huang, Yang Zhong

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He, Xiao-Ping

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Joshi, Rasesh B

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Jang, Wonjo

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McNamara, James O

dc.coverage.spatial

United States

dc.date.accessioned

2016-04-22T18:07:56Z

dc.date.issued

2015-11-04

dc.description.abstract

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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/26481038

dc.identifier

S0896-6273(15)00821-1

dc.identifier.eissn

1097-4199

dc.identifier.uri

https://hdl.handle.net/10161/11838

dc.language

eng

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Elsevier BV

dc.relation.ispartof

Neuron

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10.1016/j.neuron.2015.09.032

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Amino Acid Sequence

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Animals

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Epilepsy

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Female

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Hippocampus

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Humans

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Male

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Mice

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Mice, 129 Strain

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Mice, Inbred C57BL

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Mice, Transgenic

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Molecular Sequence Data

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Peptide Fragments

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Phospholipase C gamma

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Rats

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Rats, Sprague-Dawley

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Receptor, trkB

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Status Epilepticus

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Uncoupling Agents

dc.title

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

dc.type

Journal article

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/26481038

pubs.begin-page

484

pubs.end-page

491

pubs.issue

3

pubs.organisational-group

Basic Science Departments

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Clinical Science Departments

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Duke

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Duke Institute for Brain Sciences

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Institutes and Provost's Academic Units

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Neurobiology

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Neurology

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Neurology, Epilepsy and Sleep

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Pharmacology & Cancer Biology

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School of Medicine

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University Institutes and Centers

pubs.publication-status

Published

pubs.volume

88

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