Temporal lobe epilepsy (TLE) is a common and often devastating form of human epilepsy that lacks preventive therapy. Evidence from clinical and preclinical studies supports the idea that an episode of prolonged seizures (status epilepticus or SE) contributes to development of TLE. Defining the molecular mechanisms by which SE transforms a normal brain into an epileptic brain is essential for identifying molecular targets fo preventive therapies. Work accomplished during the current funding period revealed that transiently inhibiting the brain-derived neurotrophic factor (BDNF) receptor tyrosine kinase, TrkB, commencing following SE prevented SE-induced TLE. In preliminary studies we have discovered that global inhibition of TrkB signaling exacerbates SE-induced death of neurons, a detrimental outcome that must be mitigated. This led us to seek the downstream signaling pathway by which TrkB promotes epileptogenesis, our preliminary evidence implicating phospholipase Cy1 (PLCy1) as the dominant pathway. Our objective is to define the molecular mechanism by which SE induces TLE. To accomplish this objective, we propose to examine the effect of pharmacological uncoupling of TrkB from PLCy1 on cell death induced by SE in an adult mouse and on TLE induced by SE in a neonatal animal. We also propose to determine precisely when following SE that TrkB must be uncoupled from PLCy1 in order to prevent TLE in adults. Successful completion of the work proposed may pave the way to prevention of a subset of TLE, a common disorder of the human nervous system.

Public Health Relevance

Lack of effective prevention for common disorders of the human nervous system is a glaring unmet medical need critical to the mission of NINDS. The work proposed here represents a novel and innovative approach to uncover molecular signaling mechanisms underlying temporal lobe epilepsy. Such insights may pave the way to prevention of a subset of temporal lobe epilepsy, a common disorder of the human nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS056217-09
Application #
8759651
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2006-07-15
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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