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Chunk #33 — DISCUSSION

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Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells.
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We report that putative hESC-derived GABAergic interneurons receive synaptic inputs from both other human interneurons and from excitatory mouse projection neurons. In addition, cells with neurochemical properties of cortical interneurons adopt fairly mature physiological properties within 30 days of co-culture. Future studies will be required to address the mechanisms of accelerated in vitro maturation of the NKX2.1::GFP+ neurons on mouse cortical cultures and to determine whether species-specific timing factors are involved as suggested from our preliminary studies using hESC-derived cortical feeders. However, our data demonstrate that the proposed culture system can yield synaptically active cortical interneurons in vitro, a key prerequisite for modeling cortical interneuron pathologies in psychiatric disorders such as schizophrenia or autism. The generation of hESC-derived PV expressing neurons and the presence of relatively rapid spiking, non-accommodating neurons in these cultures is of particular interest given the implications of PV interneuron dysfunction in schizophrenia (Lewis et al., 2005). Fast-spiking PV+ cortical interneurons are observed late during primate prenatal development and continue their maturation into early adulthood (Anderson et al., 1995; Insel, 2010). Given the important role of PV+