A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.
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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.
SubjectAmino Acid Sequence
Mice, 129 Strain
Mice, Inbred C57BL
Molecular Sequence Data
Phospholipase C gamma
Published Version (Please cite this version)10.1016/j.neuron.2015.09.032
Publication InfoGu, Bin; He, Xiao-Ping; Huang, YZ; Jang, W; Joshi, Rasesh B; & McNamara, James O'Connell Sr (2015). A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus. Neuron, 88(3). pp. 484-491. 10.1016/j.neuron.2015.09.032. Retrieved from https://hdl.handle.net/10161/11838.
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Assistant Professor of Neurology
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Duke School of Medicine Professor in Neuroscience
The goal of this laboratory is to elucidate the cellular and molecular mechanisms underlying epileptogenesis, the process by which a normal brain becomes epileptic. The epilepsies constitute a group of common, serious neurological disorders, among which temporal lobe epilepsy (TLE) is the most prevalent and devastating. Many patients with severe TLE experienced an episode of prolonged seizures (status epilepticus, SE) years prior to the onset of TLE. Because induct
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