International Symposium | 19th to 22nd September


NEWroscience 2023


Candi LaSarge

Department of Anesthesia. Cincinnati Children's Hospital. University of Cincinnati. Cincinnati, USA.


mTOR Hyperactivity Initiates an Epileptogenic Cascade

The phosphatidylinositol-3-kinase (PI3K) - mammalian target of rapamycin (mTOR) pathway controls cell proliferation, growth, development, and survival. To date, numerous mutations in genes that regulate this pathway have been identified in connection with epilepsy, including loss of function mutations in the negative pathway regulators phosphatase and tensin homologue (PTEN) and tuberous sclerosis complex 1 and 2 (TSC). These mTOR pathway mutations are often present as mosaic variants in focal epilepsy and can produce lesions that range from focal cortical dysplasia to hemimegalencephaly. Unfortunately, the mechanisms underlying seizure development have yet to be fully understood. In this talk will be shown developed animal models with either a PTEN deletion from a small population of dentate granule cells or a focal cortical loss of the TSC2 gene to investigate how neurons with mTOR hyperactivation contribute to an epileptic network. Both genetic manipulations recapitulate an epilepsy phenotype that is associated with abnormal neuron development. In this model, PTEN knockout cells drive a hyperexcitable dentate, and when the knockout cell population reaches a threshold around 15%, additional secondary changes in the circuit support a shift from focal hippocampal epilepsy to a generalized seizure phenotype. Focal deletion of TSC2 from neonatal cortical excitatory neurons reliably produces a robust seizure phenotype, while initiating cortical changes that include a localized increase in vessel density. Together, data suggest an epileptogenic cascade follows gene deletion from selected populations of neurons that supports the development of spontaneous seizures. Disease severity may reflect combinatorial effects of the affected cell population size and the secondary changes initiated by the abnormal neurons.