Transsynaptic signaling by activity-dependent cleavage of neuroligin-1.
Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+ /calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity.
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Rui T
RT
Peixoto
Portia A
PA
Kunz
Hyungbae
H
Kwon
Angela M
AM
Mabb
Bernardo L
BL
Sabatini
Benjamin D
BD
Philpot
Michael D
MD
Ehlers
D000818:Animals; D000831:Animals, Newborn; D019921:Biotinylation; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002522:Chlorocebus aethiops; D003623:Dark Adaptation / Q000235:genetics; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D004558:Electric Stimulation; D018274:Electroporation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018721:Muscarinic Agonists / Q000633:toxicity; D009154:Mutation / Q000235:genetics; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017785:Photons; D010862:Pilocarpine / Q000633:toxicity; D037121:Plant Lectins / Q000235:genetics / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011247:Pregnancy; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D000097573:Red Fluorescent Protein
D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D020780:Matrix Metalloproteinase 9; D018721:Muscarinic Agonists; D019006:Neural Cell Adhesion Molecules; D010862:Pilocarpine; D037121:Plant Lectins; D011189:Potassium Chloride; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D013912:Threonine; D050598:Vesicular Glutamate Transport Protein 1; D000097573:Red Fluorescent Protein; C092350:FM 4-64; C527193:Nrxn1 protein, mouse; C093438:neuroligin 1; C034981:tomato lectin; C501830:Mmp9 protein, mouse