An increasing literature suggests that schizophrenia is associated with a reduction in hippocampal interneuron function. Thus, we posit that stem cell-derived interneuron transplants may be an effective therapeutic strategy to reduce hippocampal hyperactivity and attenuate behavioral deficits in schizophrenia. Here we used a dual-reporter embryonic stem cell line to generate enriched populations of parvalbumin (PV)- or somatostatin (SST)-positive interneurons, which were transplanted into the ventral hippocampus of the methylazoxymethanol rodent model of schizophrenia. These interneuron transplants integrate within the existing circuitry, reduce hippocampal hyperactivity and normalize aberrant dopamine neuron activity. Further, interneuron transplants alleviate behaviors that model negative and cognitive symptoms, including deficits in social interaction and cognitive inflexibility. Interestingly, PV- and SST-enriched transplants produced differential effects on behavior, with PV-enriched populations effectively normalizing all the behaviors examined. These data suggest that the stem cell-derived interneuron transplants may represent a novel therapeutic strategy for schizophrenia.
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This work was supported by the Owens Foundation and by R01 MH090067 (DL) and R01 MH066912 (SA), and R01 DA032701 (MB) from the NIH. Cell sorting was performed by the Flow Cytometry Shared Resource Facility, supported by UTHSCSA, NIH-NCI P30 CA054174-20 (CTRC at UTHSCSA) and UL1 TR001120 (CTSA grant). We would like to acknowledge Jordan Thomas for his technical assistance.
JJD and DJL participated in research design. JJD and SYB conducted experiments. JAT and SAA contributed new reagents. JJD, SYB, MJB and DJL performed the data analysis. All authors wrote or contributed to the writing of the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Donegan, J., Tyson, J., Branch, S. et al. Stem cell-derived interneuron transplants as a treatment for schizophrenia: preclinical validation in a rodent model. Mol Psychiatry 22, 1492–1501 (2017). https://doi.org/10.1038/mp.2016.121
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