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Isoform-specific cleavage of neuroligin-3 reduces synapse strength

Abstract

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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Acknowledgements

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

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Bemben, M.A., Nguyen, T.A., Li, Y. et al. Isoform-specific cleavage of neuroligin-3 reduces synapse strength. Mol Psychiatry 24, 145–160 (2019). https://doi.org/10.1038/s41380-018-0242-y

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