Every cell has a unique combination of mutations that have accumulated by imperfect DNA repair. If these somatic mutations occur in a critical early time in cerebral cortical development they can affect enough cells in the brain to impair function and result in pathophysiology. Perhaps the best demonstrated examples of somatic mutations causing pathophysiology in the human brain are seizures caused by glial and glial-neuronal tumors and by focal cortical dysplasias. The most common somatic mutations identified to date in these lesions include activating BRAF kinase mutations in approximately 30-50% of resected gangliogliomas, and activating mutations in MTOR, AKT, and PIK3CA kinases in focal cortical dysplasias. Current evidence suggests that these mutations are drivers of the underlying pathologies responsible for focal epilepsies. Consistent with the idea that focal somatic mutations in a subset of neurons and/or glia are sufficient to cause seizures, recent studies have shown that expression of mutations identified in resected human tissue in relatively small numbers of cortical neurons in mice is sufficient to cause seizures. What remains largely unknown is precisely how and whether different somatic mutations lead to neuronal hyperexcitability in cortical neurons and hypersynchrony in cortical circuits. Using novel animal models of focal somatic mutation in neural progenitors we propose to test three hypotheses focused on defining the underlying developmental, cellular and molecular causes of seizures resulting from somatic mutations in cortex: 1) cellular phenotypes and seizure severity are a function of the neocortical progenitors in which epileptogenic mutations arise, 2) elevated cortical excitability is a direct consequence of overactive MAPK/ERK and MTOR pathways in either or both neurons and astrocytes, and 3) epileptiform activity spreads from perilesional zones by altered connections to inhibitory interneuron networks that result in hypersynchronous interneuron activity.

Public Health Relevance

Every cell has a unique combination of mutations that have accumulated over time from imperfect DNA repair. Some such somatic mutations can lead to epilepsy-causing lesions in the brains of children and young adults. Results from our proposed experiments will lead to a more mechanistic understanding of how somatic mutations cause epileptogenic lesions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS104999-03
Application #
9857666
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Whittemore, Vicky R
Project Start
2018-05-01
Project End
2023-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269