Synaptic PRG-1 Modulates Excitatory Transmission via Lipid Phosphate-Mediated Signaling

Cell. 2009 Sep 18;138(6):1222-35. doi: 10.1016/j.cell.2009.06.050.

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.

Publication types

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

MeSH terms

  • Animals
  • Electroencephalography
  • Hippocampus / chemistry
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Lysophospholipids / metabolism
  • Mice
  • Mice, Knockout
  • Proteoglycans / analysis
  • Proteoglycans / genetics
  • Proteoglycans / metabolism*
  • Receptors, AMPA / metabolism
  • Receptors, Lysophosphatidic Acid / metabolism
  • Signal Transduction
  • Synapses / metabolism*
  • Vesicular Transport Proteins / analysis
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • Lysophospholipids
  • Proteoglycans
  • Receptors, AMPA
  • Receptors, Lysophosphatidic Acid
  • Vesicular Transport Proteins
  • serglycin
  • glutamate receptor ionotropic, AMPA 2
  • lysophosphatidic acid