title: Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons.
abstract: Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid-mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca(2+) influx or Ca(2+)/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca(2+)/CaM-dependent signaling pathway.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. jaewonko@yonsei.ac.kr
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
authors.forename: Gilberto J
authors.initials: GJ
authors.lastname: Soler-Llavina
authors.forename: Marc V
authors.initials: MV
authors.lastname: Fuccillo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009924:Organ Culture Techniques; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C561490:LRRTM1 protein, mouse; C561491:LRRTM2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C098004:neuroligin 3; D017871:Calcium-Calmodulin-Dependent Protein Kinases