Modeling Down Syndrome with Patient iPSCs Reveals Cellular and Migration Deficits of GABAergic Neurons

Stem Cell Reports. 2018 Apr 10;10(4):1251-1266. doi: 10.1016/j.stemcr.2018.02.001. Epub 2018 Mar 8.

Abstract

The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum. Gene expression profiling revealed altered cell migratory pathways, and correction of the PAK1 pathway mitigated the cell migration deficit in vitro. These results suggest that impaired migration of DS GABAergic neurons may contribute to the reduced number of interneurons in the cerebral cortex and hippocampus in DS patients.

Keywords: Down syndrome; GABAergic neurons; differentiation; iPSC disease modeling; migration.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Animals
  • Brain / pathology
  • Calbindin 2 / metabolism
  • Cell Differentiation / drug effects
  • Cell Movement* / drug effects
  • Cell Shape / drug effects
  • Cell Survival / drug effects
  • Down Syndrome / genetics
  • Down Syndrome / pathology*
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Interneurons / pathology
  • Mice
  • Models, Biological*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurites / pathology
  • Somatostatin / pharmacology
  • p21-Activated Kinases / metabolism

Substances

  • Actin Depolymerizing Factors
  • Calbindin 2
  • Somatostatin
  • Pak1 protein, mouse
  • p21-Activated Kinases