Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure.
Published
Journal Article
OBJECTIVE: Temporal lobe epilepsy (TLE) is a devastating disease in which seizures persist in 35% of patients despite optimal use of antiseizure drugs. Clinical and preclinical evidence implicates seizures themselves as one factor promoting epilepsy progression. What is the molecular consequence of a seizure that promotes progression? Evidence from preclinical studies led us to hypothesize that activation of tropomyosin kinase B (TrkB)-phospholipase-C-gamma-1 (PLCγ1) signaling induced by a seizure promotes epileptogenesis. METHODS: To examine the effects of inhibiting TrkB signaling on epileptogenesis following an isolated seizure, we implemented a modified kindling model in which we induced a seizure through amygdala stimulation and then used either a chemical-genetic strategy or pharmacologic methods to disrupt signaling for 2 days following the seizure. The severity of a subsequent seizure was assessed by behavioral and electrographic measures. RESULTS: Transient inhibition of TrkB-PLCγ1 signaling initiated after an isolated seizure limited progression of epileptogenesis, evidenced by the reduced severity and duration of subsequent seizures. Unexpectedly, transient inhibition of TrkB-PLCγ1 signaling initiated following a seizure also reverted a subset of animals to an earlier state of epileptogenesis. Remarkably, inhibition of TrkB-PLCγ1 signaling in the absence of a recent seizure did not reduce severity of subsequent seizures. INTERPRETATION: These results suggest a novel strategy for limiting progression or potentially ameliorating severity of TLE whereby transient inhibition of TrkB-PLCγ1 signaling is initiated following a seizure. ANN NEUROL 2019;86:939-950.
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Duke Authors
Cited Authors
- Krishnamurthy, K; Huang, YZ; Harward, SC; Sharma, KK; Tamayo, DL; McNamara, JO
Published Date
- December 2019
Published In
Volume / Issue
- 86 / 6
Start / End Page
- 939 - 950
PubMed ID
- 31525273
Pubmed Central ID
- 31525273
Electronic International Standard Serial Number (EISSN)
- 1531-8249
Digital Object Identifier (DOI)
- 10.1002/ana.25602
Language
- eng
Conference Location
- United States