Transsynaptic signaling by activity-dependent cleavage of neuroligin-1

Neuron. 2012 Oct 18;76(2):396-409. doi: 10.1016/j.neuron.2012.07.006. Epub 2012 Oct 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biotinylation
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Chlorocebus aethiops
  • Dark Adaptation / genetics
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Disease Models, Animal
  • Electric Stimulation
  • Electroporation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agents / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Female
  • Glutamic Acid / pharmacology
  • Green Fluorescent Proteins / genetics
  • Hippocampus / cytology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Muscarinic Agonists / toxicity
  • Mutation / genetics
  • Neural Cell Adhesion Molecules / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Photons
  • Pilocarpine / toxicity
  • Plant Lectins / genetics
  • Plant Lectins / metabolism
  • Potassium Chloride / pharmacology
  • Pregnancy
  • Pyridinium Compounds / metabolism
  • Quaternary Ammonium Compounds / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Status Epilepticus / chemically induced
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*
  • Threonine / genetics
  • Threonine / metabolism
  • Transfection
  • Vesicular Glutamate Transport Protein 1 / metabolism

Substances

  • Cell Adhesion Molecules, Neuronal
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • FM 4-64
  • Luminescent Proteins
  • Muscarinic Agonists
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • Plant Lectins
  • Pyridinium Compounds
  • Quaternary Ammonium Compounds
  • Vesicular Glutamate Transport Protein 1
  • neuroligin 1
  • red fluorescent protein
  • tomato lectin
  • Pilocarpine
  • Green Fluorescent Proteins
  • Threonine
  • Glutamic Acid
  • Potassium Chloride
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse