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

Nature volume 439, pages 589–593 (2006)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.

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  1. Shaoyu Ge and Eyleen L. K. Goh: *These authors contributed equally to this work

Authors and Affiliations

  1. Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Maryland, 21205, Baltimore, USA

    Shaoyu Ge, Eyleen L. K. Goh, Kurt A. Sailor, Yasuji Kitabatake, Guo-li Ming & Hongjun Song

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Correspondence to Hongjun Song.

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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)

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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). https://doi.org/10.1038/nature04404

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