ArticleMolecular psychiatry2018
Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin.
Article in Molecular psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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77 citing papers in PubMed, 132 citations in OpenAlex.
- Advancements in differentiation of induced pluripotent stem cells into specialized neuronal subtypes.Neural regeneration research · 2026Article
- Nitric Oxide-Mediated S-Nitrosylation of TSC2 Drives mTOR dysregulation across Shank3 and Cntnap2 Models of Autism Spectrum Disorder.Molecular psychiatry · 2026Article
- An Open-Source Pipeline for Calcium Imaging and All-Optical Physiology in Human Stem Cell-Derived Neurons.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Tuberous sclerosis complex.Nature reviews. Disease primers · 2026Review
- Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.Cell reports · 2025Article
- Dynamic Clamp Methods to Investigate Impaired Neuronal Excitability Associated with Autism.Journal of visualized experiments : JoVE · 2025Article
- Article
- Generation and long-term culture of human cerebellar organoids from pluripotent stem cells.Nature protocols · 2025Review
- Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome.Human molecular genetics · 2025Article
- CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability.Brain : a journal of neurology · 2025Article
- mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons.Frontiers in neuroscience · 2025Article
- Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).Exploration of drug science · 2025Article
- Perspectives in the investigation of Cockayne syndrome group B neurological disease: the utility of patient-derived brain organoid models.Journal of Zhejiang University. Science. B · 2024Review
- Non-invasive label-free imaging analysis pipeline for in situ characterization of 3D brain organoids.Scientific reports · 2024Article
- Review
- Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome.bioRxiv : the preprint server for biology · 2024Article
- Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit.Journal of neurodevelopmental disorders · 2024Article
- Calcium-Dependent Regulation of Neuronal Excitability Is Rescued in Fragile X Syndrome by a Tat-Conjugated N-Terminal Fragment of FMRP.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Non-Invasive Label-free Analysis Pipeline for In Situ Characterization of Differentiation in 3D Brain Organoid Models.Research square · 2024Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC. Our results show that hiPSC-derived PCs from patients with pathogenic TSC2 mutations displayed mTORC1 pathway hyperactivation, defects in neuronal differentiation and RNA regulation, hypoexcitability and reduced synaptic activity when compared with those derived from controls. Our gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs. We detected decreased expression of FMRP, glutamate receptor δ2 (GRID2), and pre- and post-synaptic markers such as synaptophysin and PSD95 in the TSC2-deficient hiPSC-PCs. The mTOR inhibitor rapamycin rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro. Our findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in TSC affected individuals.
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