Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons

Mol Psychiatry. 2015 Nov;20(11):1350-65. doi: 10.1038/mp.2014.141. Epub 2014 Nov 11.


An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / metabolism
  • Autistic Disorder / genetics
  • Autistic Disorder / pathology*
  • Autistic Disorder / physiopathology
  • Carboplatin / metabolism
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Child
  • Disease Models, Animal
  • Embryo, Mammalian
  • Etoposide / metabolism
  • Gene Expression Regulation / genetics
  • Humans
  • In Vitro Techniques
  • Induced Pluripotent Stem Cells / physiology
  • Inhibitory Postsynaptic Potentials / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitoxantrone / metabolism
  • Mutation / genetics
  • Neurons / metabolism
  • Neurons / pathology*
  • Prednisolone / metabolism
  • Signal Transduction / genetics
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • TRPC6 Cation Channel


  • TRPC Cation Channels
  • TRPC6 Cation Channel
  • TRPC6 protein, human
  • Etoposide
  • Prednisolone
  • Carboplatin
  • Mitoxantrone

Supplementary concepts

  • MECP protocol