Focal cortical dysplasia (FCD) is the most common underlying pathology in children with drug resistant epilepsies. DEPDC5 mutations have been increasingly recognized as the most important genetic cause in focal epilepsies with or without FCD. Using focal somatic mutagenesis approaches, we recently generated a rodent model with pathological and electrographic signatures that are highly clinically-relevant to human FCD. However, precisely how dysplastic cortex and seizures arise from Depdc5 mutation remains unknown. We propose to focus on defining the underlying genetic, cellular and circuitry mechanisms contributing to DEPDC5-related epilepsies as well as establishing the critical roles of DEPDC5 in cortical development. We will provide conceptual insights broadly relevant to understanding mTOR-related malformation of cortical development and epilepsies. Our central hypothesis is that DEPDC5 mutations in cortical progenitors generate focal intrinsic epileptogenecity through its critical roles in sculpting neural and glial development, and that inhibition of mTORC1 recruitment will restore cytoarchitectures and suppress seizures.

Public Health Relevance

The proposed project studies the pathogenesis of focal cortical dysplasia and seizures caused by DEPDC5 mutations. Dr. Yu Wang uses the combination of somatic mutagenesis, electrophysiology and molecular genetics tools to study how DEPDC5 mutations generate epileptogenic dysplasia at genetic, cellular and circuitry levels, and whether a novel strategy to inhibit mTOR recruitment can suppress seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS113824-01
Application #
9859550
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Whittemore, Vicky R
Project Start
2019-09-15
Project End
2024-05-31
Budget Start
2019-09-15
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109