Isoform-specific cleavage of neuroligin-3 reduces synapse strength

• Published in: Molecular psychiatry Vol. 24; no. 1; pp. 145 - 160
• Main Authors: Bemben, Michael A., Nguyen, Thien A., Li, Yan, Wang, Tongguang, Nicoll, Roger A., Roche, Katherine W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2019; Nature Publishing Group
• Subjects: 13/106; 14/1; 631/378; 631/80; 82; 9/74; Adhesion; Animals; Behavioral Sciences; Biological Psychology; Cell adhesion; Cell Adhesion - physiology; Cell Adhesion Molecules, Neuronal - metabolism; Cells, Cultured; Cleavage; Dismantling; Female; Glioma; Gliomas; HEK293 Cells; HeLa Cells; Hippocampus - metabolism; Humans; Kinases; Male; Medicine; Medicine & Public Health; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mitogens; Nerve Growth Factors - metabolism; Nerve Tissue Proteins - metabolism; Neuregulin-1 - metabolism; Neurons; Neurons - metabolism; Neurosciences; Pharmacotherapy; Protein Isoforms; Protein kinase C; Protein Kinase C - metabolism; Protein kinases; Proteolysis; Psychiatry; Rats; Rats, Sprague-Dawley; Synapses; Synapses - physiology; Synaptic strength; Synaptogenesis
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-018-0242-y

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.