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

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. [Display omitted] •Murine and human fibroblasts can be directly converted into GABAergic neurons•iGABA-INs and telencephalic GABAergic INs share molecular features•iGABA-INs are functional GABA-releasing inhibitory INs•Grafted iGABA-INs functionally inhibit excitatory dentate granule cells Colasante et al. identify a combination of five transcription factors that convert mouse and human fibroblasts into induced GABAergic telencephalic interneurons (iGABA-INs), which are functionally similar to bona fide GABAergic INs. Upon transplantation, iGABA-INs functionally integrate into host neuronal networks and inhibit excitatory neurons in the host hippocampus.