mGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE

Neuron. 2008 Mar 27;57(6):858-71. doi: 10.1016/j.neuron.2008.01.010.


Matrix metalloproteases (MMPs) play a role in remodeling the extracellular matrix during brain development and have been implicated in synaptic plasticity. Here, we report that a member of the neuronal pentraxin (NP) family, neuronal pentraxin receptor (NPR), undergoes regulated cleavage by the MMP tumor necrosis factor-alpha converting enzyme (TACE). NPR is enriched at excitatory synapses where it associates with AMPA-type glutamate receptors (AMPAR) and enhances synaptogenesis. However, in response to activation of group 1 mGluRs (mGluR1/5), TACE cleaves NPR and releases the pentraxin domain from its N-terminal transmembrane domain. Cleaved NPR rapidly accumulates in endosomes where it colocalizes with AMPAR. This process is necessary for mGluR1/5-dependent LTD in hippocampal and cerebellar synapses. These observations suggest that cleaved NPR functions to "capture" AMPAR for endocytosis and reveal a bifunctional role of NPs in both synapse strengthening and weakening.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • ADAM Proteins / metabolism
  • ADAM Proteins / pharmacology*
  • ADAM17 Protein
  • Animals
  • Animals, Newborn
  • C-Reactive Protein / deficiency
  • Cells, Cultured
  • Cerebellum / cytology
  • Embryo, Mammalian
  • Excitatory Amino Acid Agents / pharmacology
  • Hippocampus / cytology
  • Humans
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Inhibitory Postsynaptic Potentials / radiation effects
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / deficiency
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Neuronal Plasticity / radiation effects
  • Neurons / drug effects*
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Protein Structure, Tertiary / physiology
  • RNA, Small Interfering / pharmacology
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / metabolism*
  • Receptors, Metabotropic Glutamate / physiology*
  • Transfection


  • Excitatory Amino Acid Agents
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • neuronal pentraxin
  • neuronal pentraxin receptor
  • C-Reactive Protein
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse