The pathophysiology of epilepsy is intimately linked with imbalances of excitation and inhibition (E/I) in the brain. Although the loss of GABAergic inhibition is strongly implicated as a mechanism by which E/I imbalances arise in human epilepsy disorders, the molecular mechanisms that govern synaptic inhibition, and thereby maintain E/I balance, have been largely obscure. Recently, we discovered a novel inhibitory synaptic protein, Rogdi, whose gene is strongly linked to a human epilepsy disorder, Kohlschtter-Tnz syndrome. Preliminary data indicate that Rogdi may function either at the pre- or postsynapse where I hypothesize that it may regulate the synaptic vesicle cycle or protein trafficking. I propose to test this hypothesis and demonstrate Rogdi?s functional role at inhibitory synapses. Importantly, I will also determine if the loss of Rogdi is causal for seizures in mice. The successful completion of the proposed research will generate a new preclinical mouse model for studying Kohlschtter-Tnz syndrome and can be expected to generate an understanding of Rogdi?s molecular function and its contribution towards the etiology of a human epilepsy disorder.

Public Health Relevance

Epilepsy, the condition of spontaneous recurrent seizures, is a devastating neurological disorder. Rare genetic mutations provide unique opportunities to understand the molecular mechanisms that drive susceptibility to seizures and epilepsy. This proposed work will study a human epilepsy candidate gene and can be expected to generate a deeper understanding of the molecular mechanisms underlying epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS113738-02
Application #
9988845
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Whittemore, Vicky R
Project Start
2019-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
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