Modeling Neurodevelopmental Deficits in Tuberous Sclerosis Complex with Stem Cell Derived Neural Precursors and Neurons

  • Maria Sundberg
  • Mustafa SahinEmail author
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 25)


Tuberous sclerosis complex (TSC) is a rare genetic disorder that is caused by mutations in TSC1 or TSC2. TSC is a multi-organ disorder characterized by development of non-malignant cellular overgrowths, called hamartomas, in different organs of the body. TSC is also characterized as a neurodevelopmental disorder presenting with epilepsy and autism, and formation of cortical malformations (“tubers”), subependymal giant cell astrocytomas (SEGAs), and subependymal nodules (SENs) in the patient’s brain. In this chapter, we are going to give an overview of neural stem cell and neuronal development in TSC. In addition, we will also describe previously developed animal models of TSC that display seizures, autistic-like behaviors, and neuronal cell abnormalities in vivo, and we will compare them to disease phenotypes detected with human stem cell derived neuronal cells in vitro. We will describe the effects of TSC-mutations in different neural cell subtypes, and discuss the mitochondrial function, autophagy, and synaptic development and functional deficits in the neurons. Finally, we will review utilization of these human TSC-patient derived neuronal models for drug screening to develop new treatment options for the neurological phenotypes seen in TSC patients.


Tuberous sclerosis complex Neural stem cells Autism Epilepsy mTORC1 mTORC2 Mitochondrion Astrogliosis Synaptogenesis 



Owing to limited space, we have not quoted all literature in the field, and we apologize to those whose articles are not referenced. We would like to thank Denise McGinnis for critical reading of the manuscript. We would like to thank Ville Kujala for design and preparation of the images. The Sahin lab has received grant funding from the US National Institutes of Health (NIH) (U01-NS082320, U01-NS092595, and U54-HD090255), US Department of Defense W81XWH-15–1–0189, Nancy Lurie Marks Family Foundation, Autism Speaks, TS Alliance, National Ataxia Foundation, Harvard Stem Cell Institute, Tommy Fuss Center, Roche, Novartis, Pfizer and LAM Therapeutics.


  1. 1.
    Feliciano, D. M., Lin, T. V., Hartman, N. W., Bartley, C. M., Kubera, C., Hsieh, L., et al. (2013). A circuitry and biochemical basis for tuberous sclerosis symptoms: From epilepsy to neurocognitive deficits. International Journal of Developmental Neuroscience, 31, 667–678.PubMedGoogle Scholar
  2. 2.
    Orlova, K. A., & Crino, P. B. (2010). The tuberous sclerosis complex. Annals of the New York Academy of Sciences, 1184, 87–105.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Sahin, M., Henske, E. P., Manning, B. D., Ess, K. C., Bissler, J. J., Klann, E., et al. (2016). Advances and future directions for tuberous sclerosis complex research: recommendations from the 2015 strategic planning conference. Pediatric Neurology, 60, 1–12.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006). The tuberous sclerosis complex. The New England Journal of Medicine, 355, 1345–1356.PubMedGoogle Scholar
  5. 5.
    Lipton, J. O., & Sahin, M. (2014). The neurology of mTOR. Neuron, 84, 275–291.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Chu-Shore, C. J., Major, P., Camposano, S., Muzykewicz, D., & Thiele, E. A. (2010). The natural history of epilepsy in tuberous sclerosis complex. Epilepsia, 51, 1236–1241.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Jeste, S. S., Sahin, M., Bolton, P., Ploubidis, G. B., & Humphrey, A. (2008). Characterization of autism in young children with tuberous sclerosis complex. Journal of Child Neurology, 23, 520–525.PubMedGoogle Scholar
  8. 8.
    Richards, C., Jones, C., Groves, L., Moss, J., & Oliver, C. (2015). Prevalence of autism spectrum disorder phenomenology in genetic disorders: A systematic review and meta-analysis. Lancet Psychiatry, 2, 909–916.PubMedGoogle Scholar
  9. 9.
    Bruining, H., Eijkemans, M. J., Kas, M. J., Curran, S. R., Vorstman, J. A., & Bolton, P. F. (2014). Behavioral signatures related to genetic disorders in autism. Molecular Autism, 5, 11.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Jeste, S. S., Varcin, K. J., Hellemann, G. S., Gulsrud, A. C., Bhatt, R., Kasari, C., et al. (2016). Symptom profiles of autism spectrum disorder in tuberous sclerosis complex. Neurology, 87, 766–772.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Chamberlain, S. J., Chen, P. F., Ng, K. Y., Bourgois-Rocha, F., Lemtiri-Chlieh, F., Levine, E. S., et al. (2010). Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proceedings of the National Academy of Sciences of the United States of America, 107, 17668–17673.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Chiu, F. L., Lin, J. T., Chuang, C. Y., Chien, T., Chen, C. M., Chen, K. H., et al. (2015). Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington’s disease iPSCs. Human Molecular Genetics, 24, 6066–6079.PubMedGoogle Scholar
  13. 13.
    Cooper, O., Seo, H., Andrabi, S., Guardia-Laguarta, C., Graziotto, J., Sundberg, M., et al. (2012). Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Science Translational Medicine, 4, 141ra190.Google Scholar
  14. 14.
    Marchetto, M. C., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143, 527–539.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Pasca, S. P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A. M., et al. (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Medicine, 17, 1657–1662.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Sundberg, M., Bogetofte, H., Lawson, T., Jansson, J., Smith, G., Astradsson, A., et al. (2013). Improved cell therapy protocols for Parkinson’s disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cells, 31, 1548–1562.PubMedGoogle Scholar
  17. 17.
    Sundberg, M., Tochitsky, I., Buchholz, D. E., Winden, K., Kujala, V., Kapur, K., et al. (2018). Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin. Molecular Psychiatry, 23(11), 2167–2183.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Wainger, B. J., Kiskinis, E., Mellin, C., Wiskow, O., Han, S. S., Sandoe, J., et al. (2014). Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Reports, 7, 1–11.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Woodard, C. M., Campos, B. A., Kuo, S. H., Nirenberg, M. J., Nestor, M. W., Zimmer, M., et al. (2014). iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson’s disease. Cell Reports, 9, 1173–1182.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. Cell, 169, 361–371.PubMedGoogle Scholar
  21. 21.
    Dibble, C. C., Elis, W., Menon, S., Qin, W., Klekota, J., Asara, J. M., et al. (2012). TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Molecular Cell, 47, 535–546.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Inoki, K., Li, Y., Xu, T., & Guan, K. L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & Development, 17, 1829–1834.Google Scholar
  23. 23.
    Huang, W., Zhu, P. J., Zhang, S., Zhou, H., Stoica, L., Galiano, M., et al. (2013). mTORC2 controls actin polymerization required for consolidation of long-term memory. Nature Neuroscience, 16, 441–448.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Thomanetz, V., Angliker, N., Cloetta, D., Lustenberger, R. M., Schweighauser, M., Oliveri, F., et al. (2013). Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. The Journal of Cell Biology, 201, 293–308.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009). Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nature Biotechnology, 27, 275–280.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Gerrard, L., Rodgers, L., & Cui, W. (2005). Differentiation of human embryonic stem cells to neural lineages in adherent culture by blocking bone morphogenetic protein signaling. Stem Cells, 23, 1234–1241.PubMedGoogle Scholar
  29. 29.
    Costa, V., Aigner, S., Vukcevic, M., Sauter, E., Behr, K., Ebeling, M., et al. (2016). mTORC1 inhibition corrects neurodevelopmental and synaptic alterations in a human stem cell model of tuberous sclerosis. Cell Reports, 15, 86–95.PubMedGoogle Scholar
  30. 30.
    Cho, S. W., Kim, S., Kim, J. M., & Kim, J. S. (2013). Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nature Biotechnology, 31, 230–232.PubMedGoogle Scholar
  31. 31.
    Horii, T., Tamura, D., Morita, S., Kimura, M., & Hatada, I. (2013). Generation of an ICF syndrome model by efficient genome editing of human induced pluripotent stem cells using the CRISPR system. International Journal of Molecular Sciences, 14, 19774–19781.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Hou, Z., Zhang, Y., Propson, N. E., Howden, S. E., Chu, L. F., Sontheimer, E. J., et al. (2013). Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis. Proceedings of the National Academy of Sciences of the United States of America, 110, 15644–15649.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Mussolino, C., Morbitzer, R., Lutge, F., Dannemann, N., Lahaye, T., & Cathomen, T. (2011). A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Research, 39, 9283–9293.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhang, Y., Pak, C., Han, Y., Ahlenius, H., Zhang, Z., Chanda, S., et al. (2013). Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron, 78, 785–798.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Feliciano, D. M., Quon, J. L., Su, T., Taylor, M. M., & Bordey, A. (2012). Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion. Human Molecular Genetics, 21, 799–810.PubMedGoogle Scholar
  36. 36.
    Magri, L., Cambiaghi, M., Cominelli, M., Alfaro-Cervello, C., Cursi, M., Pala, M., et al. (2011). Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell, 9, 447–462.PubMedGoogle Scholar
  37. 37.
    Zhou, J., Shrikhande, G., Xu, J., McKay, R. M., Burns, D. K., Johnson, J. E., et al. (2011). Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes & Development, 25, 1595–1600.Google Scholar
  38. 38.
    Li, Y., Cao, J., Chen, M., Li, J., Sun, Y., Zhang, Y., et al. (2017). Abnormal neural progenitor cells differentiated from induced pluripotent stem cells partially mimicked development of TSC2 neurological abnormalities. Stem Cell Reports, 8, 883–893.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Ma, J., Yu, Z., Qu, W., Tang, Y., Zhan, Y., Ding, C., et al. (2010). Proliferation and differentiation of neural stem cells are selectively regulated by knockout of cyclin D1. Journal of Molecular Neuroscience, 42, 35–43.PubMedGoogle Scholar
  40. 40.
    Sundberg, M., Savola, S., Hienola, A., Korhonen, L., & Lindholm, D. (2006). Glucocorticoid hormones decrease proliferation of embryonic neural stem cells through ubiquitin-mediated degradation of cyclin D1. The Journal of Neuroscience, 26, 5402–5410.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Mirzaa, G., Dodge, N. N., Glass, I., Day, C., Gripp, K., Nicholson, L., et al. (2004). Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus: A rare brain malformation syndrome associated with mental retardation and seizures. Neuropediatrics, 35, 353–359.PubMedGoogle Scholar
  42. 42.
    Mirzaa, G. M., Parry, D. A., Fry, A. E., Giamanco, K. A., Schwartzentruber, J., Vanstone, M., et al. (2014). De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nature Genetics, 46, 510–515.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Courchesne, E., Mouton, P. R., Calhoun, M. E., Semendeferi, K., Ahrens-Barbeau, C., Hallet, M. J., et al. (2011). Neuron number and size in prefrontal cortex of children with autism. JAMA, 306, 2001–2010.PubMedGoogle Scholar
  44. 44.
    Redcay, E., & Courchesne, E. (2005). When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biological Psychiatry, 58, 1–9.Google Scholar
  45. 45.
    Crowell, B., Lee, G. H., Nikolaeva, I., Dal Pozzo, V., & D’Arcangelo, G. (2015). Complex neurological phenotype in mutant mice lacking Tsc2 in excitatory neurons of the developing forebrain(123). Eneuro, 2.
  46. 46.
    Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., et al. (2012). Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature, 488, 647–651.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Choi, Y. J., Di Nardo, A., Kramvis, I., Meikle, L., Kwiatkowski, D. J., Sahin, M., et al. (2008). Tuberous sclerosis complex proteins control axon formation. Genes & Development, 22, 2485–2495.Google Scholar
  48. 48.
    Buccoliero, A. M., Franchi, A., Castiglione, F., Gheri, C. F., Mussa, F., Giordano, F., et al. (2009). Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study. Neuropathology, 29, 25–30.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Grajkowska, W., Kotulska, K., Jurkiewicz, E., & Matyja, E. (2010). Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathologica, 48, 139–149.PubMedGoogle Scholar
  50. 50.
    Grajkowska, W., Kotulska, K., Jurkiewicz, E., Roszkowski, M., Daszkiewicz, P., Jozwiak, S., et al. (2011). Subependymal giant cell astrocytomas with atypical histological features mimicking malignant gliomas. Folia Neuropathologica, 49, 39–46.PubMedGoogle Scholar
  51. 51.
    Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., et al. (1998). A clinicopathological study of autism. Brain, 121(Pt 5), 889–905.PubMedGoogle Scholar
  52. 52.
    Limperopoulos, C., Bassan, H., Gauvreau, K., Robertson Jr., R. L., Sullivan, N. R., Benson, C. B., et al. (2007). Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics, 120, 584–593.PubMedGoogle Scholar
  53. 53.
    Skefos, J., Cummings, C., Enzer, K., Holiday, J., Weed, K., Levy, E., et al. (2014). Regional alterations in purkinje cell density in patients with autism. PLoS One, 9, e81255.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Whitney, E. R., Kemper, T. L., Bauman, M. L., Rosene, D. L., & Blatt, G. J. (2008). Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: A stereological experiment using calbindin-D28k. Cerebellum, 7, 406–416.PubMedGoogle Scholar
  55. 55.
    Reith, R. M., McKenna, J., Wu, H., Hashmi, S. S., Cho, S. H., Dash, P. K., et al. (2013). Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiology of Disease, 51, 93–103.PubMedGoogle Scholar
  56. 56.
    Muguruma, K., Nishiyama, A., Ono, Y., Miyawaki, H., Mizuhara, E., Hori, S., et al. (2010). Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. Nature Neuroscience, 13, 1171–1180.PubMedGoogle Scholar
  57. 57.
    Muguruma, K., Nishiyama, A., Kawakami, H., Hashimoto, K., & Sasai, Y. (2015). Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Reports, 10, 537–550.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Wang, S., Wang, B., Pan, N., Fu, L., Wang, C., Song, G., et al. (2015). Differentiation of human induced pluripotent stem cells to mature functional Purkinje neurons. Scientific Reports, 5, 9232.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Morino, H., Matsuda, Y., Muguruma, K., Miyamoto, R., Ohsawa, R., Ohtake, T., et al. (2015). A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Molecular Brain, 8, 89.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Grabole, N., Zhang, J. D., Aigner, S., Ruderisch, N., Costa, V., Weber, F. C., et al. (2016). Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model. Genome Medicine, 8, 94.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Wong, M., & Crino, P. B. (2012). Tuberous sclerosis and epilepsy: Role of astrocytes. Glia, 60, 1244–1250.PubMedGoogle Scholar
  62. 62.
    Zamanian, J. L., Xu, L., Foo, L. C., Nouri, N., Zhou, L., Giffard, R. G., et al. (2012). Genomic analysis of reactive astrogliosis. The Journal of Neuroscience, 32, 6391–6410.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Boer, K., Crino, P. B., Gorter, J. A., Nellist, M., Jansen, F. E., Spliet, W. G., et al. (2010). Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors. Brain Pathology, 20, 704–719.PubMedGoogle Scholar
  64. 64.
    Zhang, B., Zou, J., Rensing, N. R., Yang, M., & Wong, M. (2015). Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiology of Disease, 80, 70–79.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Tyler, W. A., Gangoli, N., Gokina, P., Kim, H. A., Covey, M., Levison, S. W., et al. (2009). Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. The Journal of Neuroscience, 29, 6367–6378.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Guardiola-Diaz, H. M., Ishii, A., & Bansal, R. (2012). Erk1/2 MAPK and mTOR signaling sequentially regulates progression through distinct stages of oligodendrocyte differentiation. Glia, 60, 476–486.PubMedGoogle Scholar
  67. 67.
    Tyler, W. A., Jain, M. R., Cifelli, S. E., Li, Q., Ku, L., Feng, Y., et al. (2011). Proteomic identification of novel targets regulated by the mammalian target of rapamycin pathway during oligodendrocyte differentiation. Glia, 59, 1754–1769.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Arulrajah, S., Ertan, G., Jordan, L., Tekes, A., Khaykin, E., Izbudak, I., et al. (2009). Magnetic resonance imaging and diffusion-weighted imaging of normal-appearing white matter in children and young adults with tuberous sclerosis complex. Neuroradiology, 51, 781–786.PubMedGoogle Scholar
  69. 69.
    Makki, M. I., Chugani, D. C., Janisse, J., & Chugani, H. T. (2007). Characteristics of abnormal diffusivity in normal-appearing white matter investigated with diffusion tensor MR imaging in tuberous sclerosis complex. AJNR. American Journal of Neuroradiology, 28, 1662–1667.PubMedGoogle Scholar
  70. 70.
    Peters, J. M., Sahin, M., Vogel-Farley, V. K., Jeste, S. S., Nelson 3rd, C. A., Gregas, M. C., et al. (2012). Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex. Academic Radiology, 19, 17–25.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Carson, R. P., Kelm, N. D., West, K. L., Does, M. D., Fu, C., Weaver, G., et al. (2015). Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors. Annals of Clinical Translational Neurology, 2, 1041–1054.PubMedGoogle Scholar
  72. 72.
    Lebrun-Julien, F., Bachmann, L., Norrmen, C., Trotzmuller, M., Kofeler, H., Ruegg, M. A., et al. (2014). Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. The Journal of Neuroscience, 34, 8432–8448.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Bercury, K. K., Dai, J., Sachs, H. H., Ahrendsen, J. T., Wood, T. L., & Macklin, W. B. (2014). Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination. The Journal of Neuroscience, 34, 4466–4480.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Ercan, E., Han, J. M., Di Nardo, A., Winden, K., Han, M. J., Hoyo, L., et al. (2017). Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. The Journal of Experimental Medicine, 214, 681–697.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Meikle, L., Talos, D. M., Onda, H., Pollizzi, K., Rotenberg, A., Sahin, M., et al. (2007). A mouse model of tuberous sclerosis: Neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. The Journal of Neuroscience, 27, 5546–5558.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Douvaras, P., Wang, J., Zimmer, M., Hanchuk, S., O’Bara, M. A., Sadiq, S., et al. (2014). Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells. Stem Cell Reports, 3, 250–259.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Nistor, G. I., Totoiu, M. O., Haque, N., Carpenter, M. K., & Keirstead, H. S. (2005). Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia, 49, 385–396.PubMedGoogle Scholar
  78. 78.
    Stacpoole, S. R., Spitzer, S., Bilican, B., Compston, A., Karadottir, R., Chandran, S., et al. (2013). High yields of oligodendrocyte lineage cells from human embryonic stem cells at physiological oxygen tensions for evaluation of translational biology. Stem Cell Reports, 1, 437–450.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Sundberg, M., Hyysalo, A., Skottman, H., Shin, S., Vemuri, M., Suuronen, R., et al. (2011). A xeno-free culturing protocol for pluripotent stem oligodendrocyte precursor cell production. Regenerative Medicine, 6, 449–460.PubMedGoogle Scholar
  80. 80.
    Wang, S., Bates, J., Li, X., Schanz, S., Chandler-Militello, D., Levine, C., et al. (2013). Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell, 12, 252–264.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Goldman, S. A., & Kuypers, N. J. (2015). How to make an oligodendrocyte. Development, 142, 3983–3995.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Nadadhur, A. G., Alsaqati, M., Gasparotto, L., Cornelissen-Steijger, P., van Hugte, E., Dooves, S., et al. (2019). Neuron-Glia interactions increase neuronal phenotypes in tuberous sclerosis complex patient iPSC-Derived models. Stem Cell Reports, 12(1), 42–56.Google Scholar
  83. 83.
    Ebrahimi-Fakhari, D., Saffari, A., Wahlster, L., DiNardo, A., Turner, D., Lewis Jr., T. L., et al. (2016). Impaired mitochondrial dynamics and mitophagy in neuronal models of tuberous sclerosis complex. Cell Reports, 17, 2162.PubMedGoogle Scholar
  84. 84.
    Di Nardo, A., Kramvis, I., Cho, N., Sadowski, A., Meikle, L., Kwiatkowski, D. J., et al. (2009). Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. The Journal of Neuroscience, 29, 5926–5937.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Sheng, R., & Qin, Z. H. (2015). The divergent roles of autophagy in ischemia and preconditioning. Acta Pharmacologica Sinica, 36, 411–420.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Pickrell, A. M., & Youle, R. J. (2015). The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron, 85, 257–273.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Tan, C. C., Yu, J. T., Tan, M. S., Jiang, T., Zhu, X. C., & Tan, L. (2014). Autophagy in aging and neurodegenerative diseases: Implications for pathogenesis and therapy. Neurobiology of Aging, 35, 941–957.PubMedGoogle Scholar
  88. 88.
    Lee, K. M., Hwang, S. K., & Lee, J. A. (2013). Neuronal autophagy and neurodevelopmental disorders. Experimental Neurobiology, 22, 133–142.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Kim, J., Kundu, M., Viollet, B., & Guan, K. L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology, 13, 132–141.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Tang, G., Gudsnuk, K., Kuo, S. H., Cotrina, M. L., Rosoklija, G., Sosunov, A., et al. (2014). Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 83, 1131–1143.PubMedPubMedCentralGoogle Scholar
  91. 91.
    McMahon, J., Huang, X., Yang, J., Komatsu, M., Yue, Z., Qian, J., et al. (2012). Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis. The Journal of Neuroscience, 32, 15704–15714.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Parkhitko, A., Myachina, F., Morrison, T. A., Hindi, K. M., Auricchio, N., Karbowniczek, M., et al. (2011). Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proceedings of the National Academy of Sciences of the United States of America, 108, 12455–12460.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Di Nardo, A., Wertz, M. H., Kwiatkowski, E., Tsai, P. T., Leech, J. D., Greene-Colozzi, E., et al. (2014). Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Human Molecular Genetics, 23, 3865–3874.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Weisenfeld, N. I., Peters, J. M., Tsai, P. T., Prabhu, S. P., Dies, K. A., Sahin, M., et al. (2013). A magnetic resonance imaging study of cerebellar volume in tuberous sclerosis complex. Pediatric Neurology, 48, 105–110.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Constantino, J. N. (2011). The quantitative nature of autistic social impairment. Pediatric Research, 69, 55R–62R.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Happe, F., & Ronald, A. (2008). The ‘fractionable autism triad’: A review of evidence from behavioural, genetic, cognitive and neural research. Neuropsychology Review, 18, 287–304.PubMedGoogle Scholar
  97. 97.
    Sundberg, M., & Sahin, M. (2015). Cerebellar development and autism Spectrum disorder in tuberous sclerosis complex. Journal of Child Neurology, 30, 1954–1962.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Ekinci, O., Arman, A. R., Isik, U., Bez, Y., & Berkem, M. (2010). EEG abnormalities and epilepsy in autistic spectrum disorders: Clinical and familial correlates. Epilepsy & Behavior, 17, 178–182.Google Scholar
  99. 99.
    Parmeggiani, A., Barcia, G., Posar, A., Raimondi, E., Santucci, M., & Scaduto, M. C. (2010). Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev, 32, 783–789.PubMedGoogle Scholar
  100. 100.
    Viscidi, E. W., Triche, E. W., Pescosolido, M. F., McLean, R. L., Joseph, R. M., Spence, S. J., et al. (2013). Clinical characteristics of children with autism spectrum disorder and co-occurring epilepsy. PLoS One, 8, e67797.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Backman, S. A., Stambolic, V., Suzuki, A., Haight, J., Elia, A., Pretorius, J., et al. (2001). Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nature Genetics, 29, 396–403.PubMedGoogle Scholar
  102. 102.
    Goffin, A., Hoefsloot, L. H., Bosgoed, E., Swillen, A., & Fryns, J. P. (2001). PTEN mutation in a family with Cowden syndrome and autism. American Journal of Medical Genetics, 105, 521–524.PubMedGoogle Scholar
  103. 103.
    Kwon, C. H., Luikart, B. W., Powell, C. M., Zhou, J., Matheny, S. A., Zhang, W., et al. (2006). Pten regulates neuronal arborization and social interaction in mice. Neuron, 50, 377–388.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Takeuchi, K., Gertner, M. J., Zhou, J., Parada, L. F., Bennett, M. V., & Zukin, R. S. (2013). Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism. Proceedings of the National Academy of Sciences of the United States of America, 110, 4738–4743.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Winden, K. D., Sundberg, M., Yang, C., Wafa, S. M. A., Dwyer, S., Chen, P. F., et al. (2019). Biallelic mutations in TSC2 lead to abnormalities associated with cortical tubers in human iPSC-Derived neurons. J Neurosci, 39(47), 9294–9305.Google Scholar
  106. 106.
    Waltereit, R., Japs, B., Schneider, M., de Vries, P. J., & Bartsch, D. (2011). Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. Behavior Genetics, 41, 364–372.PubMedGoogle Scholar
  107. 107.
    Schneider, M., de Vries, P. J., Schonig, K., Rossner, V., & Waltereit, R. (2017). mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus. European Archives of Psychiatry and Clinical Neuroscience, 267, 455–463.PubMedGoogle Scholar
  108. 108.
    Yuan, E., Tsai, P. T., Greene-Colozzi, E., Sahin, M., Kwiatkowski, D. J., & Malinowska, I. A. (2012). Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features. Human Molecular Genetics, 21, 4286–4300.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Kelly, E., Schaeffer, S. M., Dhamne, S. C., Lipton, J. O., Lindemann, L., Honer, M., et al. (2018). mGluR5 modulation of behavioral and epileptic phenotypes in a mouse model of tuberous sclerosis complex. Neuropsychopharmacology, 43, 1457–1465.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Meikle, L., Pollizzi, K., Egnor, A., Kramvis, I., Lane, H., Sahin, M., et al. (2008). Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: Effects on mTORC1 and Akt signaling lead to improved survival and function. The Journal of Neuroscience, 28, 5422–5432.PubMedPubMedCentralGoogle Scholar
  111. 111.
    McMahon, J. J., Yu, W., Yang, J., Feng, H., Helm, M., McMahon, E., et al. (2015). Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice. Neurobiology of Disease, 73, 296–306.PubMedGoogle Scholar
  112. 112.
    Singh, S. K., & Eroglu, C. (2013). Neuroligins provide molecular links between syndromic and nonsyndromic autism. Science Signaling, 6, re4.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Yan, J., Oliveira, G., Coutinho, A., Yang, C., Feng, J., Katz, C., et al. (2005). Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Molecular Psychiatry, 10, 329–332.PubMedGoogle Scholar
  114. 114.
    Etherton, M., Foldy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M., et al. (2011). Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proceedings of the National Academy of Sciences of the United States of America, 108, 13764–13769.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Kahle, K. T., Khanna, A. R., Duan, J., Staley, K. J., Delpire, E., & Poduri, A. (2016). The KCC2 Cotransporter and human epilepsy: Getting excited about inhibition. The Neuroscientist, 22, 555–562.PubMedGoogle Scholar
  116. 116.
    Moore, Y. E., Kelley, M. R., Brandon, N. J., Deeb, T. Z., & Moss, S. J. (2017). Seizing control of KCC2: A new therapeutic target for epilepsy. Trends in Neurosciences, 40, 555–571.PubMedGoogle Scholar
  117. 117.
    Tang, X., Kim, J., Zhou, L., Wengert, E., Zhang, L., Wu, Z., et al. (2016). KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proceedings of the National Academy of Sciences of the United States of America, 113, 751–756.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Shibata, H., Huynh, D. P., & Pulst, S. M. (2000). A novel protein with RNA-binding motifs interacts with ataxin-2. Human Molecular Genetics, 9, 1303–1313.PubMedGoogle Scholar
  119. 119.
    Bhalla, K., Phillips, H. A., Crawford, J., McKenzie, O. L., Mulley, J. C., Eyre, H., et al. (2004). The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. Journal of Human Genetics, 49, 308–311.PubMedGoogle Scholar
  120. 120.
    Bucan, M., Abrahams, B. S., Wang, K., Glessner, J. T., Herman, E. I., Sonnenblick, L. I., et al. (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics, 5, e1000536.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Gai, X., Xie, H. M., Perin, J. C., Takahashi, N., Murphy, K., Wenocur, A. S., et al. (2012). Rare structural variation of synapse and neurotransmission genes in autism. Molecular Psychiatry, 17, 402–411.PubMedGoogle Scholar
  122. 122.
    Philippe, A., Martinez, M., Guilloud-Bataille, M., Gillberg, C., Rastam, M., Sponheim, E., et al. (1999). Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Human Molecular Genetics, 8, 805–812.PubMedGoogle Scholar
  123. 123.
    Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466, 368–372.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Ascano Jr., M., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., et al. (2012). FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature, 492, 382–386.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y., Mele, A., Fraser, C. E., et al. (2011). FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell, 146, 247–261.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Corbin, F., Bouillon, M., Fortin, A., Morin, S., Rousseau, F., & Khandjian, E. W. (1997). The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes. Human Molecular Genetics, 6, 1465–1472.PubMedGoogle Scholar
  127. 127.
    Davidovic, L., Jaglin, X. H., Lepagnol-Bestel, A. M., Tremblay, S., Simonneau, M., Bardoni, B., et al. (2007). The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules. Human Molecular Genetics, 16, 3047–3058.PubMedGoogle Scholar
  128. 128.
    Dictenberg, J. B., Swanger, S. A., Antar, L. N., Singer, R. H., & Bassell, G. J. (2008). A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Developmental Cell, 14, 926–939.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Feng, Y., Absher, D., Eberhart, D. E., Brown, V., Malter, H. E., & Warren, S. T. (1997). FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. Molecular Cell, 1, 109–118.PubMedGoogle Scholar
  130. 130.
    Fridell, R. A., Benson, R. E., Hua, J., Bogerd, H. P., & Cullen, B. R. (1996). A nuclear role for the fragile X mental retardation protein. The EMBO Journal, 15, 5408–5414.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Ling, S. C., Fahrner, P. S., Greenough, W. T., & Gelfand, V. I. (2004). Transport of Drosophila fragile X mental retardation protein-containing ribonucleoprotein granules by kinesin-1 and cytoplasmic dynein. Proceedings of the National Academy of Sciences of the United States of America, 101, 17428–17433.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Doherty, C., Goh, S., Young Poussaint, T., Erdag, N., & Thiele, E. A. (2005). Prognostic significance of tuber count and location in tuberous sclerosis complex. Journal of Child Neurology, 20, 837–841.PubMedGoogle Scholar
  133. 133.
    Jansen, F. E., Vincken, K. L., Algra, A., Anbeek, P., Braams, O., Nellist, M., et al. (2008). Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology, 70, 916–923.Google Scholar
  134. 134.
    Zeng, L. H., Xu, L., Gutmann, D. H., & Wong, M. (2008). Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Annals of Neurology, 63, 444–453.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Krueger, D. A., Wilfong, A. A., Holland-Bouley, K., Anderson, A. E., Agricola, K., Tudor, C., et al. (2013). Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Annals of Neurology, 74, 679–687.PubMedGoogle Scholar
  136. 136.
    Krueger, D. A., Wilfong, A. A., Mays, M., Talley, C. M., Agricola, K., Tudor, C., et al. (2016). Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology, 87, 2408–2415.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Samueli, S., Abraham, K., Dressler, A., Groppel, G., Muhlebner-Fahrngruber, A., Scholl, T., et al. (2016). Efficacy and safety of Everolimus in children with TSC - associated epilepsy - pilot data from an open single-center prospective study. Orphanet Journal of Rare Diseases, 11, 145.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Overwater, I. E., Rietman, A. B., Bindels-de Heus, K., Looman, C. W., Rizopoulos, D., Sibindi, T. M., et al. (2016). Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. Neurology, 87, 1011–1018.PubMedGoogle Scholar
  139. 139.
    Bissler, J. J., McCormack, F. X., Young, L. R., Elwing, J. M., Chuck, G., Leonard, J. M., et al. (2008). Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. The New England Journal of Medicine, 358, 140–151.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Franz, D. N., Leonard, J., Tudor, C., Chuck, G., Care, M., Sethuraman, G., et al. (2006). Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Annals of Neurology, 59, 490–498.PubMedGoogle Scholar
  141. 141.
    Buckmaster, P. S., Ingram, E. A., & Wen, X. (2009). Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. The Journal of Neuroscience, 29, 8259–8269.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of NeurologyF.M. Kirby Center for Neurobiology, Boston Children’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations