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Isoform-specific cleavage of neuroligin-3 reduces synapse strength

Molecular Psychiatry (2018) | Download Citation


The assembly and maintenance of synapses are dynamic processes that require bidirectional contacts between the pre- and postsynaptic structures. A network of adhesion molecules mediate this physical interaction between neurons. How synapses are disassembled and if there are distinct mechanisms that govern the removal of specific adhesion molecules remain unclear. Here, we report isoform-specific proteolytic cleavage of neuroligin-3 in response to synaptic activity and protein kinase C signaling resulting in reduced synapse strength. Although neuroligin-1 and neuroligin-2 are not directly cleaved by this pathway, when heterodimerized with neuroligin-3, they too undergo proteolytic cleavage. Thus protein kinase C-dependent cleavage is mediated through neuroligin-3. Recent studies on glioma implicate the neuroligin-3 ectodomain as a mitogen. Here we demonstrate: (1) there are mechanisms governing specific adhesion molecule remodeling; (2) neuroligin-3 is a key regulator of neuroligin cleavage events; and (3) there are two cleavage pathways; basal and activity-dependent that produce the mitogenic form of neuroligin-3.

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  1. 1.

    Dalva MB, McClelland AC, Kayser MS. Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci. 2007;8:206–20.

  2. 2.

    Craig AM, Kang Y. Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol. 2007;17:43–52.

  3. 3.

    Sudhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455:903–11.

  4. 4.

    Bemben MA, Shipman SL, Nicoll RA, Roche KW. The cellular and molecular landscape of neuroligins. Trends Neurosci. 2015;38:496–505.

  5. 5.

    Budreck EC, Scheiffele P. Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur J Neurosci. 2007;26:1738–48.

  6. 6.

    Shipman SL, Schnell E, Hirai T, Chen BS, Roche KW, Nicoll RA. Functional dependence of neuroligin on a new non-PDZ intracellular domain. Nat Neurosci. 2011;14:718–26.

  7. 7.

    Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007;318:71–6.

  8. 8.

    Yan J, Oliveira G, Coutinho A, Yang C, Feng J, Katz C, et al. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry. 2005;10:329–32.

  9. 9.

    Bemben MA, Shipman SL, Hirai T, Herring BE, Li Y, Badger JD 2nd, et al. CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses. Nat Neurosci. 2014;17:56–64.

  10. 10.

    Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K, et al. Activity-dependent proteolytic cleavage of neuroligin-1. Neuron. 2012;76:410–22.

  11. 11.

    Peixoto RT, Kunz PA, Kwon H, Mabb AM, Sabatini BL, Philpot BD, et al. Transsynaptic signaling by activity-dependent cleavage of neuroligin-1. Neuron. 2012;76:396–409.

  12. 12.

    Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 2010;29:3020–32.

  13. 13.

    Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012;31:3157–68.

  14. 14.

    Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 2015;161:803–16.

  15. 15.

    Venkatesh HS, Tam LT, Woo PJ, Lennon J, Nagaraja S, Gillespie SM, et al. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature. 2017;549:533–7.

  16. 16.

    Bemben MA, Nguyen QA, Wang T, Li Y, Nicoll RA, Roche KW. Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses. Proc Natl Acad Sci USA. 2015;112:2551–6.

  17. 17.

    Park MJ, Park IC, Hur JH, Rhee CH, Choe TB, Yi DH, et al. Protein kinase C activation by phorbol ester increases in vitro invasion through regulation of matrix metalloproteinases/tissue inhibitors of metalloproteinases system in D54 human glioblastoma cells. Neurosci Lett. 2000;290:201–4.

  18. 18.

    Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8:221–33.

  19. 19.

    Conant K, Allen M, Lim ST. Activity dependent CAM cleavage and neurotransmission. Front Cell Neurosci. 2015;9:305.

  20. 20.

    Song JY, Ichtchenko K, Sudhof TC, Brose N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci USA. 1999;96:1100–5.

  21. 21.

    Varoqueaux F, Jamain S, Brose N. Neuroligin 2 is exclusively localized to inhibitory synapses. Eur J Cell Biol. 2004;83:449–56.

  22. 22.

    Nguyen QA, Horn ME, Nicoll RA. Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses. eLife. 2016; 5.

  23. 23.

    Poulopoulos A, Soykan T, Tuffy LP, Hammer M, Varoqueaux F, Brose N. Homodimerization and isoform-specific heterodimerization of neuroligins. Biochem J. 2012;446:321–30.

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We are grateful to John D. Badger III and Dan Qin, as well as other members of the Roche and Nicoll labs, for technical assistance and for discussions on the project and manuscript. We thank Dr. Avindra Nath for providing human embryonic neuron cultures, and the NINDS light imaging facility for their expertise. This research was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program and the National Institute of Mental Health grant number 5 R37 MH038256.

Author contributions

MAB designed constructs and experiments, performed biochemical experiments, conducted all imaging and electrophysiology experiments, and executed data analysis. MAB and KWR wrote the manuscript. TAN helped design and perform biochemical experiments and conducted all biochemical experiments in rodent brains. YL performed and analyzed all mass spectrometry data. TW provided human neurons. KWR and RAN helped design experiments and supervised the project. All authors provided comments on the manuscript.

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  1. Receptor Biology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA

    • Michael A. Bemben
    • , Thien A. Nguyen
    •  & Katherine W. Roche
  2. Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, San Francisco, CA, 94158, USA

    • Michael A. Bemben
    •  & Roger A. Nicoll
  3. Department of Pharmacology and Physiology, Georgetown University, Washington D.C., WA, 20057, USA

    • Thien A. Nguyen
  4. Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA

    • Yan Li
  5. Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, 20892, USA

    • Tongguang Wang


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Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Michael A. Bemben or Katherine W. Roche.

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