Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming

Cell Stem Cell. 2015 Dec 3;17(6):719-734. doi: 10.1016/j.stem.2015.09.002. Epub 2015 Oct 29.


Transplantation of GABAergic interneurons (INs) can provide long-term functional benefits in animal models of epilepsy and other neurological disorders. Whereas GABAergic INs can be differentiated from embryonic stem cells, alternative sources of GABAergic INs may be more tractable for disease modeling and transplantation. We identified five factors (Foxg1, Sox2, Ascl1, Dlx5, and Lhx6) that convert mouse fibroblasts into induced GABAergic INs (iGABA-INs) possessing molecular signatures of telencephalic INs. Factor overexpression activates transcriptional networks required for GABAergic fate specification. iGABA-INs display progressively maturing firing patterns comparable to cortical INs, form functional synapses, and release GABA. Importantly, iGABA-INs survive and mature upon being grafted into mouse hippocampus. Optogenetic stimulation demonstrated functional integration of grafted iGABA-INs into host circuitry, triggering inhibition of host granule neuron activity. These five factors also converted human cells into functional GABAergic INs. These properties suggest that iGABA-INs have potential for disease modeling and cell-based therapeutic approaches to neurological disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Cellular Reprogramming*
  • Coculture Techniques
  • Embryonic Stem Cells / cytology
  • Fibroblasts / cytology*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Hippocampus / cytology
  • Humans
  • Interneurons / cytology*
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Prosencephalon / cytology*
  • SOXB1 Transcription Factors / metabolism
  • Synapses / metabolism
  • Telencephalon / cytology
  • Transcription, Genetic
  • gamma-Aminobutyric Acid / metabolism*


  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • Foxg1 protein, mouse
  • Nerve Tissue Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • gamma-Aminobutyric Acid

Associated data

  • GEO/GSE74065