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Neuroligin-1–dependent competition regulates cortical synaptogenesis and synapse number

Nature Neuroscience volume 15, pages 1667–1674 (2012)Cite this article

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Abstract

Members of the neuroligin family of cell-adhesion proteins are found at excitatory and inhibitory synapses and are mutated in some familial forms of autism spectrum disorders. Although they display synaptogenic properties in heterologous systems, the function of neuroligins in vivo in the regulation of synapse formation and synapse number has been difficult to establish. We found that neuroligin-1 (NL1), which is located at excitatory postsynaptic densities, regulates activity-dependent synaptogenesis and mature synapse number on cortical layer 2/3 pyramidal neurons in vivo. However, synapse number was not sensitive to absolute NL1 levels but instead depended on transcellular differences in the relative amounts of NL1. These effects were independent of the cell-autonomous regulation of NMDA-type glutamate receptors by absolute levels of NL1. Our data indicate that transcellular competitive processes govern synapse formation and number in developing cortex and that NL1 has a central function in these processes.

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Figure 1: Sparse knockdown of NL1, but not global knockout, reduces synapse number and spine density in cortical layer 2/3 pyramidal neurons.
Figure 2: NL1 modulates NMDAR-mediated currents and Ca2+ signaling at individual postsynaptic terminals.
Figure 3: Constitutive NL1 knockout lowers NMDAR uEPSCs and Ca2+ transients.
Figure 4: NL1 regulates activity-dependent spinogenesis.
Figure 5: Spine density of Nlgn1−/− neurons in vitro is affected by presence of neighboring Nlgn1+/+ neurons.
Figure 6: Variable Nlgn1 mRNA in across cortical neurons.
Figure 7: Relative levels of NL1 determine spine number in vivo via intercellular interactions.

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Acknowledgements

We thank members of the Sabatini laboratory for their constructive comments on the manuscript. We also thank A. Giessel, J.F. Sturgill and B. Bloodgood for helping us with data analysis. We are grateful to F. Varoqueaux and N. Brose (Max Planck Institute for Experimental Medicine) for providing mouse NL1 expression vector and Nlgn1+/− mice. This work was supported by US National Institutes of Health grant R01NS064583 (to C.G.), a Leonard and Isabelle Goldenson Research Fellowship (to Y.K.) and a SFARI grant from the Simons Foundation (to B.L.S.).

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  1. Hyung-Bae Kwon

    Present address: Present address: Max Planck Florida Institute, Jupiter, Florida, USA.,

Authors and Affiliations

  1. Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

    Hyung-Bae Kwon, Yevgenia Kozorovitskiy, Rui T Peixoto, Nazia Akhtar, Jessica L Saulnier & Bernardo L Sabatini

  2. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA

    Won-Jong Oh & Chenghua Gu

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Contributions

H.-B.K. and B.L.S. conceived the study. H.-B.K. performed experiments and data analysis. N.A. and J.L.S. performed western blot analysis and cell culture and provided technical assistance. W.-J.O. and C.G. designed and performed the experiments shown in Figure 6. Y.K. performed and designed the experiments shown in Figure 7e–g with design assistance from R.T.P.

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Correspondence to Bernardo L Sabatini.

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Kwon, HB., Kozorovitskiy, Y., Oh, WJ. et al. Neuroligin-1–dependent competition regulates cortical synaptogenesis and synapse number. Nat Neurosci 15, 1667–1674 (2012). https://doi.org/10.1038/nn.3256

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