Temporal and Mosaic Tsc1 Deletion in the Developing Thalamus Disrupts Thalamocortical Circuitry, Neural Function, and Behavior

• Spatially and temporally controlled Tsc1 deletion mimics genetic mosaicism
• Early Tsc1 deletion causes abnormal thalamic neuron physiology
• Tsc1 mutant thalamic circuits alter somatosensory cortex patterning and function
• Tsc1 deletion within developing thalamus causes abnormal grooming and seizures

SummaryTuberous sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest that the thalamus may be affected in tuberous sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E) 12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. In contrast, only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism.