Article

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

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Abstract

Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (RO1 DA031833 to C.E., RO1 DE022743 to R.-R.J., F31 NS092419 to J.A.S.) and a Holland Trice Brain Research Award to C.E. K.T.B. was supported by Foerster-Bernstein Family and the Hartwell Foundation. We thank the NHLBI light microscopy core for STED imaging. We thank N. Allen, M. Bagnat, D. Silver and S. Soderling for critical reading of the manuscript.

Author information

Affiliations

  1. Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Jeff A. Stogsdill
    • , Juan Ramirez
    • , Katherine T. Baldwin
    • , Eray Enustun
    • , Tiffany Ejikeme
    •  & Cagla Eroglu
  2. Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Di Liu
    • , Yong Ho Kim
    •  & Ru-Rong Ji
  3. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Ru-Rong Ji
    •  & Cagla Eroglu
  4. Duke Institute for Brain Sciences (DIBS), Durham, North Carolina 27710, USA

    • Ru-Rong Ji
    •  & Cagla Eroglu

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Contributions

J.A.S. and C.E. designed the experiments and wrote the paper. All authors reviewed and edited the manuscript. J.A.S. performed experiments and analysed data. J.A.S. and J.R. performed immunohistochemistry and cell/synapse count analysis. R.-R.J. designed and D.L. and Y.-H.K. performed and analysed the electrophysiology experiments. J.A.S. and K.T.B. performed western blot analysis. J.A.S., E.E., and T.E. performed in vitro experiments and analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cagla Eroglu.

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    This file contains Supplementary Methods, Supplementary References and Supplementary Figure 1, the uncropped scans.

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