GABA regulates synaptic integration of newly generated neurons in the adult brain


Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain1,2,3,4,5,6,7,8. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions1,2,3,4,5,6,7,8. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content9,10,11,12. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Development of newborn DGCs in the adult mice.
Figure 2: Nature of GABA-induced activation in newborn DGCs in the adult brain.
Figure 3: Synaptic integration of newborn DGCs in the adult brain.
Figure 4: Dendritic development of newborn DGCs in the adult brain.


  1. 1

    Kempermann, G. & Gage, F. H. New nerve cells for the adult brain. Sci. Am. 280, 48–53 (1999)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Fuchs, E. & Gould, E. Mini-review: in vivo neurogenesis in the adult brain: regulation and functional implications. Eur. J. Neurosci. 12, 2211–2214 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Temple, S. & Alvarez-Buylla, A. Stem cells in the adult mammalian central nervous system. Curr. Opin. Neurobiol. 9, 135–141 (1999)

    CAS  Article  Google Scholar 

  4. 4

    Doetsch, F. & Hen, R. Young and excitable: the function of new neurons in the adult mammalian brain. Curr. Opin. Neurobiol. 15, 121–128 (2005)

    CAS  Article  Google Scholar 

  5. 5

    Ming, G.-l. & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005)

    CAS  Article  Google Scholar 

  6. 6

    van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Carleton, A., Petreanu, L. T., Lansford, R., Alvarez-Buylla, A. & Lledo, P. M. Becoming a new neuron in the adult olfactory bulb. Nature Neurosci. 6, 507–518 (2003)

    CAS  Article  Google Scholar 

  8. 8

    Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Ben-Ari, Y. Excitatory actions of GABA during development: the nature of the nurture. Nature Rev. Neurosci. 3, 728–739 (2002)

    CAS  Article  Google Scholar 

  10. 10

    Owens, D. F. & Kriegstein, A. R. Is there more to GABA than synaptic inhibition? Nature Rev. Neurosci. 3, 715–727 (2002)

    CAS  Article  Google Scholar 

  11. 11

    Delpire, E. Cation-chloride cotransporters in neuronal communication. News Physiol. Sci. 15, 309–312 (2000)

    CAS  PubMed  Google Scholar 

  12. 12

    Payne, J. A., Rivera, C., Voipio, J. & Kaila, K. Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci. 26, 199–206 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Overstreet, L. S. & Westbrook, G. L. Paradoxical reduction of synaptic inhibition by vigabatrin. J. Neurophysiol. 86, 596–603 (2001)

    CAS  Article  Google Scholar 

  14. 14

    Nusser, Z. & Mody, I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 87, 2624–2628 (2002)

    CAS  Article  Google Scholar 

  15. 15

    Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nature Rev. Neurosci. 6, 215–229 (2005)

    CAS  Article  Google Scholar 

  16. 16

    Wang, L. P., Kempermann, G. & Kettenmann, H. A subpopulation of precursor cells in the mouse dentate gyrus receives synaptic GABAergic input. Mol. Cell. Neurosci. 29, 181–189 (2005)

    CAS  Article  Google Scholar 

  17. 17

    Wadiche, L. O., Bromberg, D. A., Bensen, A. L. & Westbrook, G. L. GABAergic signalling to newborn neurons in dentate gyrus. J. Neurophysiol. 94, 4528–4532 (2005)

    CAS  Article  Google Scholar 

  18. 18

    Wang, D. D., Krueger, D. D. & Bordey, A. GABA depolarizes neuronal progenitors of the postnatal subventricular zone via GABAA receptor activation. J. Physiol. (Lond.) 550, 785–800 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Liu, X., Wang, Q., Haydar, T. F. & Bordey, A. Nonsynaptic GABA signalling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nature Neurosci. 8, 1179–1187 (2005)

    CAS  Article  Google Scholar 

  20. 20

    Tozuka, Y., Fukuda, S., Namba, T., Seki, T. & Hisatsune, T. GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47, 803–815 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Owens, D. F., Boyce, L. H., Davis, M. B. & Kriegstein, A. R. Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J. Neurosci. 16, 6414–6423 (1996)

    CAS  Article  Google Scholar 

  22. 22

    Paddison, P. J., Caudy, A. A., Bernstein, E., Hannon, G. J. & Conklin, D. S. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 16, 948–958 (2002)

    CAS  Article  Google Scholar 

  23. 23

    Delpire, E., Lu, J., England, R., Dull, C. & Thorne, T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nature Genet. 22, 192–195 (1999)

    CAS  Article  Google Scholar 

  24. 24

    Chadderton, P., Margrie, T. W. & Hausser, M. Integration of quanta in cerebellar granule cells during sensory processing. Nature 428, 856–860 (2004)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Semyanov, A., Walker, M. C., Kullmann, D. M. & Silver, R. A. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269 (2004)

    CAS  Article  Google Scholar 

  26. 26

    Chavas, J., Forero, M. E., Collin, T., Llano, I. & Marty, A. Osmotic tension as a possible link between GABAA receptor activation and intracellular calcium elevation. Neuron 44, 701–713 (2004)

    CAS  Article  Google Scholar 

  27. 27

    Cline, H. T. Dendritic arbor development and synaptogenesis. Curr. Opin. Neurobiol. 11, 118–126 (2001)

    CAS  Article  Google Scholar 

  28. 28

    Wong, R. O. & Ghosh, A. Activity-dependent regulation of dendritic growth and patterning. Nature Rev. Neurosci. 3, 803–812 (2002)

    CAS  Article  Google Scholar 

  29. 29

    Tyzio, R. et al. Membrane potential of CA3 hippocampal pyramidal cells during postnatal development. J. Neurophysiol. 90, 2964–2972 (2003)

    Article  Google Scholar 

  30. 30

    Verheugen, J. A., Fricker, D. & Miles, R. Noninvasive measurements of the membrane potential and GABAergic action in hippocampal interneurons. J. Neurosci. 19, 2546–2555 (1999)

    CAS  Article  Google Scholar 

Download references


We would like to thank C. F. Stevens, F. H. Gage, R. Huganir, K.-W. Yau and J. Bischofberger for comments and suggestions, L-h. Liu for technical support, E. Delpire for Nkcc1 knockout mice and mouse Nkcc1 cDNA, and N. Gaiano, D. Sun, D. K. Ma and D. Pradhan for reagents and help. This work was supported by the National Institute of Health (H.S.), Klingenstein Fellowship Awards in the Neurosciences (G-l.M. and H.S.), the Whitehall Foundation (G-l.M.) and The Robert Packard Center for ALS Research at Johns Hopkins (H.S.). Author Contributions S.G. did virus injection and electrophysiology, E.L.K.G. engineered retroviral constructs and did characterization, K.A.S. did immunohistochemistry and confocal imaging analysis, and Y.K. helped with molecular biology. G-l.M. and H.S. are senior authors and were responsible for project planning. All authors discussed the results and commented on the manuscript.

Author information



Corresponding author

Correspondence to Hongjun Song.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Characterization of neuronal development of retroviral- labelled newborn cells in the dentate gyrus of adult mice. (PDF 9195 kb)

Supplementary Figure 2

Characterization of the tonic GABA currents in newly generated DGCs in the dentate gyrus of adult mice. (PDF 5190 kb)

Supplementary Figure 3

Measurements of the reversal potential for GABA-induced currents and the membrane potentials of newborn DGCs. (PDF 3898 kb)

Supplementary Figure 4

Intracellular chloride concentrations in newly generated DGCs in the adult brain. (PDF 467 kb)

Supplementary Figure 5

Validation of the efficiency and specificity of shRNA-mediated knockdown of the NKCC1 expression. (PDF 1122 kb)

Supplementary Figure 6

Defects in the synaptic integration of newborn neurons in the adult brain of NKCC1 germ-line knockout mice. (PDF 1544 kb)

Supplementary Figure 7

Promotion of dendritic growth of newborn DGCs by the GABAAR agonist in the adult brain. (PDF 214 kb)

Supplementary Table

Physiological properties of mature granule cells under different conditions. (DOC 22 kb)

Supplementary Methods

Detailed methodology. (DOC 107 kb)

Supplementary Figure Legends

Figure legends for Supplementary Figures 1–6. (DOC 28 kb)

Supplementary Video 1

Three-dimensional-reconstruction of Z-series confocal images of proliferating newborn cells in the dentate gyrus of adult mice at 2 days after retroviral injection. (MOV 9488 kb)

Supplementary Video 2

Three-dimensional-reconstruction of Z-series confocal images of newborn neurons in the dentate gyrus of adult mice at 28 days after retroviral injection. (MOV 9546 kb)

Supplementary Video Legends

Legends for Supplementary Videos 1 and 2. (DOC 19 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ge, S., Goh, E., Sailor, K. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing