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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Zhao, C., Deng, W. & Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008)
Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009)
Ming, G. L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702 (2011)
Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & Alvarez-Buylla, A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001)
Lagace, D. C. et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J. Neurosci. 27, 12623–12629 (2007)
Imayoshi, I. et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nature Neurosci. 11, 1153–1161 (2008)
Encinas, J. M. et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8, 566–579 (2011)
Dranovsky, A. et al. Experience dictates stem cell fate in the adult hippocampus. Neuron 70, 908–923 (2011)
Bonaguidi, M. A. et al. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145, 1142–1155 (2011)
Encinas, J. M., Vaahtokari, A. & Enikolopov, G. Fluoxetine targets early progenitor cells in the adult brain. Proc. Natl Acad. Sci. USA 103, 8233–8238 (2006)
Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nature Rev. Neurosci. 6, 215–229 (2005)
Bekkers, J. M. & Stevens, C. F. NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341, 230–233 (1989)
Caraiscos, V. B. et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. Proc. Natl Acad. Sci. USA 101, 3662–3667 (2004)
Jagasia, R. et al. GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J. Neurosci. 29, 7966–7977 (2009)
Freund, T. F. & Buzsaki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996)
Taniguchi, H. et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71, 995–1013 (2011)
Cardin, J. A. et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459, 663–667 (2009)
Ibi, D. et al. Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J. Neurochem. 105, 921–932 (2008)
Andang, M. et al. Histone H2AX-dependent GABAA receptor regulation of stem cell proliferation. Nature 451, 460–464 (2008)
Fernando, R. N. et al. Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells. Proc. Natl Acad. Sci. USA 108, 5837–5842 (2011)
Lolova, I. & Davidoff, M. Age-related morphological and morphometrical changes in parvalbumin- and calbindin-immunoreactive neurons in the rat hippocampal formation. Mech. Ageing Dev. 66, 195–211 (1992)
Satoh, J., Tabira, T., Sano, M., Nakayama, H. & Tateishi, J. Parvalbumin-immunoreactive neurons in the human central nervous system are decreased in Alzheimer’s disease. Acta Neuropathol. 81, 388–395 (1991)
Masiulis, I., Yun, S. & Eisch, A. J. The interesting interplay between interneurons and adult hippocampal neurogenesis. Mol. Neurobiol. 44, 287–302 (2011)
Knable, M. B., Barci, B. M., Webster, M. J., Meador-Woodruff, J. & Torrey, E. F. Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol. Psychiatry 9, 609–620 (2004)
Gonzalez-Burgos, G., Fish, K. N. & Lewis, D. A. GABA neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia. Neural Plast. 2011, 723184 (2011)
Andre, V., Marescaux, C., Nehlig, A. & Fritschy, J. M. Alterations of hippocampal GABAergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy. Hippocampus 11, 452–468 (2001)
Schweizer, C. et al. The γ2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses. Mol. Cell. Neurosci. 24, 442–450 (2003)
Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006)
Kim, J. Y. et al. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63, 761–773 (2009)
Schneider Gasser, E. M. et al. Immunofluorescence in brain sections: simultaneous detection of presynaptic and postsynaptic proteins in identified neurons. Nature Protocols 1, 1887–1897 (2006)
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.
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-8 and legends for Supplementary Movies 1-3. (PDF 12498 kb)
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)
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)
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)
About this article
Cite this article
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
Is High-Intensity Interval Training Suitable to Promote Neuroplasticity and Cognitive Functions after Stroke?
International Journal of Molecular Sciences (2021)
Natural and forced neurogenesis in the adult brain: Mechanisms and their possible application to treat neurological disorders
Neuroscience Research (2021)
Neuroscience & Biobehavioral Reviews (2021)
GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice
Stem Cell Research & Therapy (2021)
Loss of α7 nicotinic acetylcholine receptors in GABAergic neurons causes sex-dependent decreases in radial glia-like cell quantity and impairments in cognitive and social behavior
Brain Structure and Function (2021)