# Developmental Pathophysiology in Neocortex Caused By Somatic Mutations

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2020 · $352,188

## Abstract

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.

## Key facts

- **NIH application ID:** 9857666
- **Project number:** 5R01NS104999-03
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Joseph J LoTurco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,188
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857666

## Citation

> US National Institutes of Health, RePORTER application 9857666, Developmental Pathophysiology in Neocortex Caused By Somatic Mutations (5R01NS104999-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9857666. Licensed CC0.

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