title: Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses.
abstract: Three neuronal pentraxins are expressed in brain, the membrane-bound "neuronal pentraxin receptor" (NPR) and the secreted proteins NP1 and NARP (i.e., NP2). Neuronal pentraxins bind to AMPARs at excitatory synapses and play important, well-documented roles in the activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether neuronal pentraxins perform roles in synapses beyond modulating postsynaptic AMPAR-dependent plasticity, and whether they may even act in inhibitory synapses. Here, we show that NPR expressed in non-neuronal cells potently induces formation of both excitatory and inhibitory postsynaptic specializations in cocultured hippocampal neurons. Knockdown of NPR in hippocampal neurons, conversely, dramatically decreased assembly and function of both excitatory and inhibitory postsynaptic specializations. Overexpression of NPR rescued the NPR knockdown phenotype but did not in itself change synapse numbers or properties. However, the NPR knockdown decreased the levels of NARP, whereas NPR overexpression produced a dramatic increase in the levels of NP1 and NARP, suggesting that NPR recruits and stabilizes NP1 and NARP on the presynaptic plasma membrane. Mechanistically, NPR acted in excitatory synapse assembly by binding to the N-terminal domain of AMPARs; antagonists of AMPA and GABA receptors selectively inhibited NPR-induced heterologous excitatory and inhibitory synapse assembly, respectively, but did not affect neurexin-1β-induced synapse assembly as a control. Our data suggest that neuronal pentraxins act as signaling complexes that function as general trans-synaptic organizers of both excitatory and inhibitory synapses by a mechanism that depends, at least in part, on the activity of the neurotransmitter receptors at these synapses.
  
  
  
  Neuronal pentraxins comprise three neuronal proteins, neuronal pentraxin receptor (NPR) which is a type-II transmembrane protein on the neuronal surface, and secreted neuronal pentraxin-1 and NARP. The general functions of neuronal pentraxins at synapses have not been explored, except for their basic AMPAR binding properties. Here, we examined the functional role of NPR at synapses because it is the only neuronal pentraxin that is anchored to the neuronal cell-surface membrane. We find that NPR is a potent inducer of both excitatory and inhibitory heterologous synapses, and that knockdown of NPR in cultured neurons decreases the density of both excitatory and inhibitory synapses. Our data suggest that NPR performs a general, previously unrecognized function as a universal organizer of synapses.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, sungjinl@stanford.edu tcs1@stanford.edu.
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China, and.
authors.forename: Mengping
authors.initials: M
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China, and.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Stephan
authors.identifier: 0000-0002-4472-695X
authors.initials: S
authors.lastname: Maxeiner
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: ChangHui
authors.initials: C
authors.lastname: Pak
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Salome
authors.identifier: 0000-0003-2822-2257
authors.initials: S
authors.lastname: Calado Botelho
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Justin
authors.initials: J
authors.lastname: Trotter
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Fredrik H
authors.identifier: 0000-0001-8881-0523
authors.initials: FH
authors.lastname: Sterky
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, sungjinl@stanford.edu tcs1@stanford.edu.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018920:Coculture Techniques; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D011956:Receptors, Cell Surface; D000099153:Pentraxins
keywords: AMPAR; cell adhesion molecule; neuronal pentraxin receptor; synaptogenesis