Epilepsy affects approximately 2.3 million adults and 450,000 children in the US. Each year, 150,000 citizens are newly diagnosed with epilepsy. The estimated cost associated with epilepsies is approximately 15.5 billion in medical expenses and lost earnings (NINDS). Progress in treating disorders associated with epilepsies is severely hampered by our lack of basic knowledge related to the molecular mechanisms underlying the disorder. Our recently published work in Science, used a novel in vivo chemico-genetic approach to identify the proteome of the inhibitory postsynapse (iPSD). This study was supported by an R21 and identified a large complex of proteins that are enriched at the iPSD of GABAergic synapses of excitatory neurons. Several of these are novel proteins encoded by genes for which human mutations are known to cause epilepsies.
The specific aims of this grant build on these exciting findings and follow up on our recent study by focusing on the testable hypothesis that epilepsy-associated mutations in genes encoding proteins of the iPSD lead to seizures by impairing inhibition. We anticipate the results of these aims will bridge our knowledge gap regarding molecular mechanisms of how epilepsies emerge in vivo from abnormalities of inhibition, leading to new future directions for the prevention and possible treatments of these disorders.

Public Health Relevance

The goal of this project is to determine if mutations in novel synaptic proteins associated with human epilepsies lead to altered function of inhibitory synapses. Uncovering these molecular mechanisms of seizures can be expected to lead to better insights of disorder etiology and potential therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102456-04
Application #
9930668
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Whittemore, Vicky R
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705