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GABA A Rs and GlyRs are considered attractive drug targets for therapeutic intervention and are also increasingly recognized in the context of  in vitro  neurotoxicity (NT) and developmental neurotoxicity (DNT) testing. However, systematic human-specific GABA A R and GlyR-targeted drug screening and toxicity testing is hampered due to lack of appropriate  in vitro  models that express native GABA A Rs and GlyRs. We have established a human pluripotent stem cell line (NT2) stably expressing YFP-I152L, a halide-sensitive variant of yellow fluorescent protein (YFP), allowing for fluorescence-based functional analysis of chloride channels. Upon stimulation with retinoic acid, NT2 cells undergo neuronal differentiation and allow pharmacological and toxicological evaluation of native GABA A Rs and GlyRs at different stages of brain maturation. We applied the cell line in concentration-response experiments with the neurotransmitters GABA and glycine as well as with the drugs strychnine, picrotoxin, fipronil, lindane, bicuculline, and zinc and demonstrate that the established  in vitro  model is applicable to GABA A R and GlyR-targeted pharmacological and toxicological profiling. We quantified the proportion of GABA A R and GlyR-sensitive cells, respectively, and identified percentages of approximately 20% each within the overall populations, rendering the cells a suitable model for systematic  in vitro  GABA A R and GlyR-targeted screening in the context of drug development and NT/DNT testing.

frontiers in molecular neuroscience

A Recombinant Human Pluripotent Stem Cell Line Stably Expressing Halide-Sensitive YFP-I152L for GABAAR and GlyR-Targeted High-Throughput Drug Screening and Toxicity Testing