Understanding the role of TSC1/2 in Cerebellar Purkinje Neurons
Technical Report,01 Sep 2015,31 Aug 2018
CHILDRENS HOSPITAL, BOSTON BOSTON United States
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Tuberous sclerosis complex is a multisystem autosomal dominant disorder caused by mutations in either TSC1 or TSC2genes. Previously our group has shown that Tsc1 knock-out mice Purkinje cells are involved in the development of autistic-likefeatures for these mice. In addition, at BCH we have collected fibroblasts and derived pluripotent stem cell lines from TSC patientsand unaffected familial controls. We have developed differentiation protocol for generation of human Purkinje cellsfrom iPSCs. We have studied mTOR-pathway hyperactivation in TSC2-deficient patient iPSC-derived PCs compared to controlcells. We are also analyzing the proliferation and differentiation rate of TSC2-deficient neural precursor cells compared tocontrol cells and studying electrophysiological properties of TSC2-deficient iPSC derived Purkinje cells. According to ourpreliminary functional data, the TSC-patient iPSC-derived PCs and healthy control iPSC-derived PCs exhibit GABAergicinhibitory synaptic currents, which can be blocked with bicuculline. These cells also exhibit glutamatergic excitatory synapticcurrents, which can be blocked with CNQX. The disease phenotyping with TSC deficient iPSC-derived PCs is important for thefuture development of new pharmacotherapy for TSC-patients with autism.
- Medicine and Medical Research