Project Summary
The long-term goal of this project is to understand the mechanisms that underlie the neurological
consequences of Tuberous Sclerosis Complex (TSC). TSC is a profoundly complex genetic disorder caused
by mutations in either the TSC1 or TSC2 gene and characterized by benign tumor growth in multiple systems
in the body. TSC is associated with epilepsy in up to 90% of patients that is often refractory to surgical or
targeted pharmacological intervention. In addition to seizures, TSC-associated neurological disorders (TANDs)
are present in up to 85% and intellectual disability is present in up to 70% of patients. Interestingly, single
TSC1 or TSC2 mutations can have differential effects between affected individuals, and even identical
inherited variants can result in different disease profiles. This indicates significant heterogeneity in patient
outcomes, the mechanisms for which is currently unknown; understanding the mechanism for this difference in
prognosis will allow us to identify novel therapeutic approaches capable of modifying outcome in TSC.
We recently developed and validated a model system of this heterogeneity to improve our ability to
probe the basic biology of TSC and explore the neural network differences underlying seizures and TANDs.
Our novel mice have a germline Tsc1 heterozygous knockout which, when introduced to controlled genetic
background diversity, faithfully recapitulate patient heterogeneity in TSC outcomes with the clinically relevant
gene dosage and expression pattern. We have remarkable preliminary data showing that the same Tsc1
haploinsufficiency results in a spectrum of background-dependent differences in TSC outcomes. This spectrum
allows us to explore how networks underlying cognition and seizure are differentially affected by the same
precipitating genetic insult. We hypothesize that genetic background-associated differences in seizure
and TANDs outcomes resulting from Tsc1 haploinsufficiency will manifest as changes in neuronal
dynamics, partially mediated by aberrant astrocyte modulation of these neuronal dynamics.
We will test this hypothesis with the following aims: 1) Phenotype the repertoire of behavioral
impairments in Tsc1 haploinsufficient mice, 2) Characterize the relationship between changes in neuronal
dynamics, seizure and TANDs, 3) Describe changes in excitatory/inhibitory dynamics and explore the role of
non-neuronal populations in changes in E/I balance that underlie epilepsy.
