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Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling

Authors

  • T. Trimbuch
  • P. Beed
  • J. Vogt
  • S. Schuchmann
  • N. Maier
  • M. Kintscher
  • J. Breustedt
  • M. Schuelke
  • N. Streu
  • O. Kieselmann
  • I. Brunk
  • G. Laube
  • U. Strauss
  • A. Battefeld
  • H. Wende
  • C. Birchmeier
  • S. Wiese
  • M. Sendtner
  • H. Kawabe
  • M. Kishimoto-Suga
  • N. Brose
  • J. Baumgart
  • B. Geist
  • J. Aoki
  • N.E. Savaskan
  • A.U. Braeuer
  • J. Chun
  • O. Ninnemann
  • D. Schmitz
  • R. Nitsch

Journal

  • Cell

Citation

  • Cell 138 (6): 1222-12235

Abstract

  • Plasticity related gene-1 (PRG-1) is a brain-specific membrane protein related to lipid phosphate phosphatases, which acts in the hippocampus specifically at the excitatory synapse terminating on glutamatergic neurons. Deletion of prg-1 in mice leads to epileptic seizures and augmentation of EPSCs, but not IPSCs. In utero electroporation of PRG-1 into deficient animals revealed that PRG-1 modulates excitation at the synaptic junction. Mutation of the extracellular domain of PRG-1 crucial for its interaction with lysophosphatidic acid (LPA) abolished the ability to prevent hyperexcitability. As LPA application in vitro induced hyperexcitability in wild-type but not in LPA(2) receptor-deficient animals, and uptake of phospholipids is reduced in PRG-1-deficient neurons, we assessed PRG-1/LPA(2) receptor-deficient animals, and found that the pathophysiology observed in the PRG-1-deficient mice was fully reverted. Thus, we propose PRG-1 as an important player in the modulatory control of hippocampal excitability dependent on presynaptic LPA(2) receptor signaling.


DOI

doi:10.1016/j.cell.2009.06.050