Posted July 11, 2013
Mark Zervas, Ph.D., Brown University, Providence, Rhode Island
Tuberous Sclerosis Complex (TSC) is an inherited disorder characterized by a variety of symptoms that may range from relatively mild to severe, including benign tumors throughout the body, seizures, developmental delay, and autism. TSC results from the loss of both alleles of the TSC1 or TSC2 gene, where one bad allele is often inherited from a parent and the other allele develops a mutation during embryonic development. The timing of TSC mutations during development and the effect on disease severity are not known. Dr. Mark Zervas received funding from the Tuberous Sclerosis Complex Research Program (TSCRP) to investigate the effects of Tsc1 loss in the mouse brain at different points during embryonic development. Specifically, his team is studying the loss of Tsc1 in neurons of the developing thalamus, a relay center of the brain that provides sensory and motor inputs to the cortex.
Dr. Zervas' team used a novel mouse model to delete both Tsc1 alleles specifically in thalamic neurons at different time points in embryonic development. Overall, they found that mice with Tsc1 deletion on the 12th day of gestation (E12) had many more behavioral symptoms, such as self-grooming and seizures, than mice with Tsc1 deletion on 18th day of gestation (E18), which is just before birth. They also compared the brains of mice with Tsc1 deletion on E12 and E18 with normal mice and, consistent with the behavioral findings, found that the abnormalities resulting from Tsc1 deletion at E12 were more severe than at E18. In addition to disorganization of the thalamic projections to parts of the cortex in mice with Tsc1 deletion on E12, Dr. Zervas' team observed enlarged size and altered physiological properties of neurons lacking Tsc1. Further, the growth-regulating mTOR pathway was disrupted in 70% of neurons in mice with the Tsc1 deletion on E12 compared to only 29% in mice with the deletion on E18. The mTOR pathway is overactive in patients in TSC, and these findings may indicate a previously unknown temporal role of the mTOR pathway in brain development.
Dr. Zervas' work has demonstrated that deletion of Tsc1 in the developing thalamus leads to both behavioral symptoms and anatomical changes in the brain. He also demonstrated that the severity of this phenotype depends on the timing and distribution of neurons with Tsc1 loss during development. Dr. Zervas will continue these studies to better define the developmental window during which Tsc1 loss is the most damaging and to test the use of the mTOR inhibitor rapamycin to ameliorate the effects of Tsc1 loss in the developing thalamus.
Genetic circuit tracing, which is visualized by red labeling, was used to show the connections between the thalamus and cerebral cortex in an adult mouse brain in which Tsc1 is functional (control, left) or in which both copies of Tsc1 were deleted at an early stage of development (mutant, right). Arrowheads indicate the innervation of somatosensory barrel structures in control cortex, which are less clearly delineated in mutant cortex. Courtesy of Mark Zervas.
Normand EA, Crandall SR, Thorn CA, et al. 2013. Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior. Neuron 78:895-909. doi: 10.1016/j.neuron.2013.03.030. (external link)
Public and Technical Abstracts: Determining Changes in Neural Circuits in Tuberous Sclerosis
Public and Technical Abstracts: Temporal Loss of Tsc1: Neural Development and Brain Disease in Tuberous Sclerosis