Tuberous sclerosis (TS) is a developmental genetic disorder with an incidence of 1:6,000. TS is caused by mutations in either the Tsc1 or Tsc2 gene, resulting in a dysregulation of the mTOR pathway (figure 1). Although symptoms vary among patients, the disease typically includes neurological manisfestations such as epilepsy (90%), autism (25-50%) and intellectual disability (50%). Functional TSC1 and TSC2 form a heterodimer that inhibits the mTOR pathway, which controls a wide array of cellular functions including cellular growth, metabolism and mRNA translation (Figure 1, left). In cells with the two copies of Tsc1 deleted, there is a loss of inhibition and processes downstrem of mTOR are overactivated (Figure 1, right). Recent studies indicate that subcortical structures such as the thalamus might be involved in TS. To address the role of this structure in TS, we have previously deleted Tsc1 in the thalamus in mice at embryonic stage E12.5 and subsequently analyzed the animals’ behavior, neurological circuitry and cellular structure at the adult stage. The animals with homozygous deletion for Tsc1 in the thalamus ( Gbx2CreER, Tsc1Δ/Δ) developed abnormal overgrooming behavior, and generalized tonic-clonic seizures starting at 2 months of age in contrast to healthy controls (Gbx2CreER, Tsc1+/+). At the cellular level, the mutant thalamic neurons have been shown to have enlarged soma, aberrant physiological properties and fail to innervate cortical targets properly (Figure 2). While innervation of distinct barrels on cortical layer IV can be observed in Tsc1+/+ animals, the thalamocortical axons (TCAs) of Tsc1Δ/Δ mutants are not properly organized and barrels are indistinguishable. To better understand the effects of embryonic Tsc1 deletion we are expanding on previous findings by examining the physiological properties of the affected neurons in mice at postnatal day 20 (P20). In addition, we are in the process of analyzing the morphology of Tsc1Δ/Δ neurons and levels of expressions of specific proteins (parvalbumin and phosphorylated S6).
Voelcker, Bettina,
"Cellular phenotypes of early Tsc1 deletion in thalamocortical neurons"
(2014).
Summer Research Symposium.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/14vg-s863
Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …
