Rewiring the Injured Brain with GABA Progenitors

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Abstract Transplantation of neural progenitor cells has extraordinary potential for the treatment of many nervous system disorders. Several recent studies have shown that progenitor cells derived from the embryonic mouse medial ganglionic eminence (MGE) retain a unique ability to migrate and differentiate into GABAergic interneurons following transplantation into the juvenile or adult rodent brain. We recently demonstrated that these cells are effective in correcting memory impairments and preventing spontaneous seizures in a mouse model of traumatic brain injury. However, it is not known whether similar therapeutic effects can be achieved with clinically-relevant cell sources, such as human pluripotent stem cells. Here, we propose studies to evaluate the effect of human-derived interneurons in a pre-clinical model of traumatic brain injury. Our approach involves transplantation of human interneuron progenitors into a widely-used rodent model of closed-head injury at different stages following injury followed by in vitro patch-clamp recordings, immunofluorescence techniques and neural circuit mapping to evaluate the synaptic integration of grafted neurons. A battery of behavioral assays and video-EEG monitoring will also be applied. Two specific aims are proposed: (i) determine how human-derived GABA progenitors integrate into brain injured hippocampus, and (ii) test the therapeutic efficacy of human GABA neurons in a mouse model of traumatic brain injury. If successful, our results will help move these exciting technologies closer to the clinic by establishing relatively direct proof of concept for human interneuron transplantation to treat traumatic brain injury.