Article | Published:

Neurons born in the adult dentate gyrus form functional synapses with target cells

Nature Neuroscience volume 11, pages 901907 (2008) | Download Citation

Subjects

This article has been updated

Abstract

Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent studies have demonstrated that newborn granule cells of the adult hippocampus are postsynaptic targets of excitatory and inhibitory neurons, but evidence of synapse formation by the axons of these cells is still lacking. By combining retroviral expression of green fluorescent protein in adult-born neurons of the mouse dentate gyrus with immuno-electron microscopy, we found output synapses that were formed by labeled terminals on appropriate target cells in the CA3 area and the hilus. Furthermore, retroviral expression of channelrhodopsin-2 allowed us to light-stimulate newborn granule cells and identify postsynaptic target neurons by whole-cell recordings in acute slices. Our structural and functional evidence indicates that axons of adult-born granule cells establish synapses with hilar interneurons, mossy cells and CA3 pyramidal cells and release glutamate as their main neurotransmitter.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Change history

  • 20 July 2008

    In the version of this article initially published online, the reference to earlier figures in the legend of Figure 5 is incorrect. For the legend of Figure 5c, the correct sentence should read "...(acquisition was interrupted from 20-25 min; same cell as in Fig. 4a-e)". The error has been corrected for all versions of this article.

References

  1. 1.

    & A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology (Bethesda) 19, 253–261 (2004).

  2. 2.

    & Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005).

  3. 3.

    , & Potential role for adult neurogenesis in the encoding of time in new memories. Nat. Neurosci. 9, 723–727 (2006).

  4. 4.

    , & Adult neurogenesis and functional plasticity in neuronal circuits. Nat. Rev. Neurosci. 7, 179–193 (2006).

  5. 5.

    , & Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).

  6. 6.

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

  7. 7.

    , & Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).

  8. 8.

    et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).

  9. 9.

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

  10. 10.

    et al. Functional convergence of neurons generated in the developing and adult hippocampus. PLoS Biol. 4, e409 (2006).

  11. 11.

    , , , & A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54, 559–566 (2007).

  12. 12.

    et al. Synapse formation on neurons born in the adult hippocampus. Nat. Neurosci. 10, 727–734 (2007).

  13. 13.

    , & Spatiotemporal profile of dendritic outgrowth from newly born granule cells in the adult rat dentate gyrus. Brain Res. 1149, 30–37 (2007).

  14. 14.

    , & The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98, 407–427 (2000).

  15. 15.

    , , , & Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3–11 (2006).

  16. 16.

    Synaptic extensions from the mossy fibers of the fascia dentata. Anat. Embryol. (Berl.) 155, 241–251 (1979).

  17. 17.

    Mossy fiber synapses on glutamate decarboxylase–immunoreactive neurons: evidence for feed-forward inhibition in the CA3 region of the hippocampus. Exp. Brain Res. 75, 441–445 (1989).

  18. 18.

    & Spiny nonpyramidal neurons in the CA3 region of the rat hippocampus are glutamate-like immunoreactive and receive convergent mossy fiber input. J. Comp. Neurol. 333, 435–448 (1993).

  19. 19.

    & Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the rat hippocampus. J. Comp. Neurol. 325, 169–182 (1992).

  20. 20.

    , & Neurons, numbers and the hippocampal network. Prog. Brain Res. 83, 1–11 (1990).

  21. 21.

    , , , & GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus. J. Neurosci. 18, 3386–3403 (1998).

  22. 22.

    , , , & Millisecond timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

  23. 23.

    et al. Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc. Natl. Acad. Sci. USA 102, 17816–17821 (2005).

  24. 24.

    , & Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses. Neuron 29, 703–715 (2001).

  25. 25.

    The dual glutamatergic-GABAergic phenotype of hippocampal granule cells. Trends Neurosci. 28, 297–303 (2005).

  26. 26.

    , & Synaptic connections of dentate granule cells and hilar neurons: results of paired intracellular recordings and intracellular horseradish peroxidase injections. Neuroscience 37, 693–707 (1990).

  27. 27.

    Evidence from simultaneous intracellular recordings in rat hippocampal slices that area CA3 pyramidal cells innervate dentate hilar mossy cells. J. Neurophysiol. 72, 2167–2180 (1994).

  28. 28.

    Electrophysiological evidence that dentate hilar mossy cells are excitatory and innervate both granule cells and interneurons. J. Neurophysiol. 74, 179–194 (1995).

  29. 29.

    , & Activation of metabotropic glutamate receptor type 2/3 suppresses transmission at rat hippocampal mossy fiber synapses. J. Physiol. (Lond.) 493, 447–455 (1996).

  30. 30.

    & Development of the mossy fibers of the dentate gyrus. I. A light and electron microscopic study of the mossy fibers and their expansions. J. Comp. Neurol. 195, 51–86 (1981).

  31. 31.

    & Postnatal development of CA3 pyramidal neurons and their afferents in the Ammon's horn of rhesus monkeys. Hippocampus 5, 217–231 (1995).

  32. 32.

    et al. Similar GABAergic inputs in dentate granule cells born during embryonic and adult neurogenesis. Eur. J. Neurosci. 25, 2973–2981 (2007).

  33. 33.

    , & Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 85, 2423–2431 (2001).

  34. 34.

    et al. A monomeric red fluorescent protein. Proc. Natl. Acad. Sci. USA 99, 7877–7882 (2002).

  35. 35.

    & A potential- and time-dependent blockade of inward rectification in frog skeletal muscle fibres by barium and strontium ions. J. Physiol. (Lond.) 280, 169–191 (1978).

  36. 36.

    , & Quantal components of unitary EPSCs at the mossy fiber synapse on CA3 pyramidal cells of rat hippocampus. J. Physiol. (Lond.) 472, 615–663 (1993).

  37. 37.

    & Spontaneous and synaptic input from granule cells and the perforant path to dentate basket cells in the rat hippocampus. Hippocampus 5, 151–164 (1995).

Download references

Acknowledgements

We would like to thank J. Jepsen and N. Nashi for technical assistance, S. Herlitze for providing the ChR2 construct, L. Petreanu for helpful discussions, J. Simon for artwork, J. Fiala for providing software and M.L. Gage for helpful suggestions to improve this manuscript. We also acknowledge the support of the Picower Foundation, Lookout Foundation, McDonnell Foundation, US National Institutes of Health grants NS050217 (to F.H.G.) and NS038331 (to C.E.R.), Agencia Nacional de Promoción Científica, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), and the Howard Hughes Medical Institute (to A.F.S.). D.A.L. and G.L. were supported by fellowships from CONICET.

Author information

Author notes

    • Nicolas Toni
    •  & Diego A Laplagne

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Genetics, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

    • Nicolas Toni
    • , Chunmei Zhao
    •  & Fred H Gage
  2. Laboratory of Neuronal Plasticity, Leloir Institute–CONICET, Av. Patricias Argentinas 435, (1405) Buenos Aires, Argentina.

    • Diego A Laplagne
    • , Gabriela Lombardi
    •  & Alejandro F Schinder
  3. Department of Anatomy & Neurobiology, University of California at Irvine, School of Medicine, Irvine, California 92697-1275, USA.

    • Charles E Ribak

Authors

  1. Search for Nicolas Toni in:

  2. Search for Diego A Laplagne in:

  3. Search for Chunmei Zhao in:

  4. Search for Gabriela Lombardi in:

  5. Search for Charles E Ribak in:

  6. Search for Fred H Gage in:

  7. Search for Alejandro F Schinder in:

Contributions

N.T. contributed to the concept, designed and carried out the structural experiments, analyzed the data, and wrote the manuscript. D.A.L. contributed to the concept, designed and performed the functional experiments, analyzed the data, and wrote the manuscript. C.Z. contributed to the experimental design, provided samples for the structural experiments, carried out and analyzed confocal images of presynaptic terminals, and revised the manuscript. G.L. prepared retroviral stocks, performed immunofluorescence and obtained images of ChR2-positive neurons. C.E.R. contributed to setting up the technique for immuno-electron microscopy of GFP, the analysis of electron micrographs, and the writing and revision of the manuscript. F.H.G. and A.F.S. contributed to the concept, designed the experiments, analyzed the data, wrote the manuscript and provided financial support.

Corresponding authors

Correspondence to Fred H Gage or Alejandro F Schinder.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Table 1 and Supplementary Methods

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.2156

Further reading