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Synapse formation on neurons born in the adult hippocampus

Nature Neuroscience volume 10, pages 727–734 (2007)Cite this article

Abstract

Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the formation of the first dendritic protrusions.

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Figure 1: Density and volume of dendritic protrusions on GFP+ neurons increase with time after viral infection.
Figure 2: The motility of protrusions decreases with time after viral infection.
Figure 3: At 30 d.p.i., GFP+ neurons display ultrastructure and synaptic input typical of dentate granule neurons.
Figure 4: New neurons synapse primarily with MSBs.
Figure 5: The tips of filopodia are preferentially associated with axonal boutons.
Figure 6: The connectivity of protrusions is related to their geometry.

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References

  1. Lamprecht, R. & LeDoux, J. Structural plasticity and memory. Nat. Rev. Neurosci. 5, 45–54 (2004).

    Article  CAS  Google Scholar 

  2. Altman, J. & Das, G.D. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319–335 (1965).

    Article  CAS  Google Scholar 

  3. Eriksson, P.S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Shors, T.J. et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372–376 (2001).

    Article  CAS  Google Scholar 

  6. Saxe, M.D. et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. USA 103, 17501–17506 (2006).

    Article  CAS  Google Scholar 

  7. Madsen, T.M., Kristjansen, P.E., Bolwig, T.G. & Wortwein, G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119, 635–642 (2003).

    Article  CAS  Google Scholar 

  8. Zhao, C., Teng, E.M., Summers, R.G., Jr., Ming, G.L. & Gage, F.H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3–11 (2006).

    Article  CAS  Google Scholar 

  9. Harris, K.M. & Kater, S.B. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu. Rev. Neurosci. 17, 341–371 (1994).

    Article  CAS  Google Scholar 

  10. Petrak, L.J., Harris, K.M. & Kirov, S.A. Synaptogenesis on mature hippocampal dendrites occurs via filopodia and immature spines during blocked synaptic transmission. J. Comp. Neurol. 484, 183–190 (2005).

    Article  Google Scholar 

  11. Dunaevsky, A., Tashiro, A., Majewska, A., Mason, C. & Yuste, R. Developmental regulation of spine motility in the mammalian central nervous system. Proc. Natl. Acad. Sci. USA 96, 13438–13443 (1999).

    Article  CAS  Google Scholar 

  12. Fischer, M., Kaech, S., Knutti, D. & Matus, A. Rapid actin-based plasticity in dendritic spines. Neuron 20, 847–854 (1998).

    Article  CAS  Google Scholar 

  13. Portera-Cailliau, C., Pan, D.T. & Yuste, R. Activity-regulated dynamic behavior of early dendritic protrusions: evidence for different types of dendritic filopodia. J. Neurosci. 23, 7129–7142 (2003).

    Article  CAS  Google Scholar 

  14. Harris, K.M., Jensen, F.E. & Tsao, B. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J. Neurosci. 12, 2685–2705 (1992).

    Article  CAS  Google Scholar 

  15. Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).

    Article  CAS  Google Scholar 

  16. Takumi, Y., Ramirez-Leon, V., Laake, P., Rinvik, E. & Ottersen, O.P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat. Neurosci. 2, 618–624 (1999).

    Article  CAS  Google Scholar 

  17. Fiala, J.C., Feinberg, M., Popov, V. & Harris, K.M. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J. Neurosci. 18, 8900–8911 (1998).

    Article  CAS  Google Scholar 

  18. Ziv, N.E. & Smith, S.J. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 17, 91–102 (1996).

    Article  CAS  Google Scholar 

  19. Knott, G.W., Holtmaat, A., Wilbrecht, L., Welker, E. & Svoboda, K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat. Neurosci. 9, 1117–1124 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  23. Harris, K.M. & Stevens, J.K. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J. Neurosci. 9, 2982–2997 (1989).

    Article  CAS  Google Scholar 

  24. Schikorski, T. & Stevens, C.F. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J. Neurosci. 17, 5858–5867 (1997).

    Article  CAS  Google Scholar 

  25. Wu, G., Malinow, R. & Cline, H.T. Maturation of a central glutamatergic synapse. Science 274, 972–976 (1996).

    Article  CAS  Google Scholar 

  26. Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M. & Gage, F.H. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130, 391–399 (2003).

    Article  CAS  Google Scholar 

  27. Gould, E., Beylin, A., Tanapat, P., Reeves, A. & Shors, T.J. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260–265 (1999).

    Article  CAS  Google Scholar 

  28. Cameron, H.A., McEwen, B.S. & Gould, E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J. Neurosci. 15, 4687–4692 (1995).

    Article  CAS  Google Scholar 

  29. Balazs, R., Jorgensen, O.S. & Hack, N. N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture. Neuroscience 27, 437–451 (1988).

    Article  CAS  Google Scholar 

  30. Tashiro, A., Sandler, V.M., Toni, N., Zhao, C. & Gage, F.H. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442, 929–933 (2006).

    Article  CAS  Google Scholar 

  31. Okabe, S., Miwa, A. & Okado, H. Spine formation and correlated assembly of presynaptic and postsynaptic molecules. J. Neurosci. 21, 6105–6114 (2001).

    Article  CAS  Google Scholar 

  32. Majewska, A.K., Newton, J.R. & Sur, M. Remodeling of synaptic structure in sensory cortical areas in vivo. J. Neurosci. 26, 3021–3029 (2006).

    Article  CAS  Google Scholar 

  33. Shepherd, G.M., Raastad, M. & Andersen, P. General and variable features of varicosity spacing along unmyelinated axons in the hippocampus and cerebellum. Proc. Natl. Acad. Sci. USA 99, 6340–6345 (2002).

    Article  CAS  Google Scholar 

  34. Trachtenberg, J.T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).

    Article  CAS  Google Scholar 

  35. Kirov, S.A. & Harris, K.M. Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated. Nat. Neurosci. 2, 878–883 (1999).

    Article  CAS  Google Scholar 

  36. Richards, D.A. et al. Glutamate induces the rapid formation of spine head protrusions in hippocampal slice cultures. Proc. Natl. Acad. Sci. USA 102, 6166–6171 (2005).

    Article  CAS  Google Scholar 

  37. Kullmann, D.M. & Asztely, F. Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci. 21, 8–14 (1998).

    Article  CAS  Google Scholar 

  38. Harris, K.M. How multiple-synapse boutons could preserve input specificity during an interneuronal spread of LTP. Trends Neurosci. 18, 365–369 (1995).

    Article  CAS  Google Scholar 

  39. Chklovskii, D.B., Mel, B.W. & Svoboda, K. Cortical rewiring and information storage. Nature 431, 782–788 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Jessberger, S. & Kempermann, G. Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur. J. Neurosci. 18, 2707–2712 (2003).

    Article  Google Scholar 

  42. De Paola, V. et al. Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex. Neuron 49, 861–875 (2006).

    Article  CAS  Google Scholar 

  43. Shepherd, G.M. & Harris, K.M. Three-dimensional structure and composition of CA3→CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J. Neurosci. 18, 8300–8310 (1998).

    Article  CAS  Google Scholar 

  44. Toni, N., Buchs, P.A., Nikonenko, I., Bron, C.R. & Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999).

    Article  CAS  Google Scholar 

  45. Geinisman, Y., Berry, R.W., Disterhoft, J.F., Power, J.M. & Van der Zee, E.A. Associative learning elicits the formation of multiple-synapse boutons. J. Neurosci. 21, 5568–5573 (2001).

    Article  CAS  Google Scholar 

  46. Friedlander, M.J., Martin, K.A. & Wassenhove-McCarthy, D. Effects of monocular visual deprivation on geniculocortical innervation of area 18 in cat. J. Neurosci. 11, 3268–3288 (1991).

    Article  CAS  Google Scholar 

  47. Consiglio, A. et al. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. Proc. Natl. Acad. Sci. USA 101, 14835–14840 (2004).

    Article  CAS  Google Scholar 

  48. van Praag, H., Christie, B.R., Sejnowski, T.J. & Gage, F.H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 96, 13427–13431 (1999).

    Article  CAS  Google Scholar 

  49. Kempermann, G., Kuhn, H.G. & Gage, F.H. Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc. Natl. Acad. Sci. USA 94, 10409–10414 (1997).

    Article  CAS  Google Scholar 

  50. Capani, F., Martone, M.E., Deerinck, T.J. & Ellisman, M.H. Selective localization of high concentrations of F-actin in subpopulations of dendritic spines in rat central nervous system: a three-dimensional electron microscopic study. J. Comp. Neurol. 435, 156–170 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Harris and J. Fiala for 3D reconstruction software (http://www.synapses.bu.edu), R. Tsien (University of California, San Diego) for the gift of mRFP1, Y. Jones and J. Jepsen for technical assistance, J. Simon for artwork, and T. Shikorski and M.L. Gage for comments on the manuscript. N.T. is supported by the Human Science Frontier Program Organization and the Swiss National Science Foundation, F.H.G. is supported by the US National Institutes of Health (NIH) NS050217-02, and a research grant from the Picower and the Lookout Foundations. Some of this work was conducted at the National Center for Microscopy and Imaging Research supported by NIH RRP41-04050 to M.H.E.

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Authors and Affiliations

  1. Laboratory of Genetics, the Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Nicolas Toni, E Matthew Teng, James B Aimone, Chunmei Zhao, Antonella Consiglio, Henriette van Praag & Fred H Gage

  2. National Center for Microscopy and Imaging Research, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Eric A Bushong, Maryann E Martone & Mark H Ellisman

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  1. Nicolas Toni
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Contributions

N.T. conceived the study, performed the experiments, analyzed the data and prepared the manuscript. E.M.T. helped with confocal microscopy and electron tomography data collection and analyses. E.A.B. provided technical expertise for intracellular injections. J.B.A. provided help with the filopodia study. C.Z. performed the live imaging experiment. A.C. provided the lentivirus. H.v.P. provided the Moloney virus construct and technical expertise. M.E.M. contributed to the analyses of the tomography data. M.H.E. contributed to the tomography experiment and provided support for all the electron microscopy experiments. F.H.G. discussed the experiments and the data, revised the manuscript and provided financial support.

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Correspondence to Fred H Gage.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Dendritic spines from new neurons are apposed to perforant path axonal boutons. (PDF 19885 kb)

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Toni, N., Teng, E., Bushong, E. et al. Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10, 727–734 (2007). https://doi.org/10.1038/nn1908

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