A somatic mutation is a genetic mutation that occurs as a cell divides in the developing body. If there is a genetic mutation that occurs during the division, this would be contained to the cell that the mutation occurred in and the other cells that this cell helped to create afterwards. There is evidence of somatic diversity in the brain, which means that specific brain cell populations have a genetic mutation in their DNA not associated with other brain cells or organs in the body. Some of these somatic mutations in the developing brain have been linked to focal cortical malformations associated with pediatric drug-resistant epilepsy.
To better understand how somatic mutations could impact epilepsy and brain circuits, Dr. Gamboa has created a mouse model that causes brain cell-specific genetic mutations that activate the mTOR pathway during cortical development. There are many studies that observe a frequent hyperactivation of mTOR signaling in epilepsy. For example, seizures associated with Tuberous Sclerosis, a rare genetic epilepsy syndrome, is treated by mTOR inhibitors. In this research proposal, she will explore how somatic mutations in the mTOR pathway in a contained population of neurons result in network abnormalities that lead to epilepsy. The disease mechanisms that arise from this research could lay the groundwork for new therapeutic approaches.