Abstract
Adult neurogenesis arises from neural stem cells within specialized niches1,2,3. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival1,3. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells4,5,6,7,8,9 (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis9 of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division8. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.
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Acknowledgements
We thank L. H. Tsai for initial help in the study; members of the Song and Ming laboratories for discussion; H. Davoudi for help; and Q. Hussaini, Y. Cai and L. Liu for technical support. This work was supported by grants from the National Institutes of Health (NIH) (NS047344) to H.S., the NIH (NS048271, HD069184), the National Alliance for Research on Schizophrenia and Depression and the Adelson Medical Research Foundation to G.L.M., the NIH (MH089111) to B.L., the NIH (AG040209) and New York State Stem Cell Science and the Ellison Medical Foundation to G.E., and by postdoctoral fellowships from the Life Sciences Research Foundation to J.S. and from the Maryland Stem Cell Research Fund to J.S., C.Z. and K.C.
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J.S. led the project and contributed to all aspects. C.Z., M.A.B., G.J.S., D.H. and K.C. helped with some experiments. Y.G. and S.G. contributed reagents. J.H. provided SST-Cre mice. G.E. provided nestin–GFP mice. K.D. and K.M. provided initial help on optogenetic tools. B.L. provided γ2f/f mice. J.S., G-l.M. and H.S. designed experiments and wrote the paper.
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Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-8 and legends for Supplementary Movies 1-3. (PDF 12498 kb)
Supplementary Movie 1
This movie shows the close association between GFP+ RGLs and GAD67+ terminals of PV+ interneurons in the adult dentate gyrus (see Supplementary Information file for full legend). (MOV 21258 kb)
Supplementary Movie 2
This movie shows the lack of interaction between SST+ interneurons and RGLs in the adult dentate gyrus (see Supplementary Information file for full legend). (MOV 20099 kb)
Supplementary Movie 3
This movie shows that a single PV+ interneuron has the capacity to regulate a large number of RGLs in the adult dentate gyrus (see Supplementary Information file for full legend). (MOV 15377 kb)
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Song, J., Zhong, C., Bonaguidi, M. et al. Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature 489, 150–154 (2012). https://doi.org/10.1038/nature11306
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DOI: https://doi.org/10.1038/nature11306
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