TY - JOUR
T1 - Synaptic PRG-1 Modulates Excitatory Transmission via Lipid Phosphate-Mediated Signaling
AU - Trimbuch, Thorsten
AU - Beed, Prateep
AU - Vogt, Johannes
AU - Schuchmann, Sebastian
AU - Maier, Nikolaus
AU - Kintscher, Michael
AU - Breustedt, Jörg
AU - Schuelke, Markus
AU - Streu, Nora
AU - Kieselmann, Olga
AU - Brunk, Irene
AU - Laube, Gregor
AU - Strauss, Ulf
AU - Battefeld, Arne
AU - Wende, Hagen
AU - Birchmeier, Carmen
AU - Wiese, Stefan
AU - Sendtner, Michael
AU - Kawabe, Hiroshi
AU - Kishimoto-Suga, Mika
AU - Brose, Nils
AU - Baumgart, Jan
AU - Geist, Beate
AU - Aoki, Junken
AU - Savaskan, Nic E.
AU - Bräuer, Anja U.
AU - Chun, Jerold
AU - Ninnemann, Olaf
AU - Schmitz, Dietmar
AU - Nitsch, Robert
N1 - Funding Information:
The authors thank James Ari Liebkowsky for correcting the manuscript; Denis Lajkó, Katja Rösler, Berit Söhl-Kielczynski, and Bernd Hesse-Niessen for technical assistance; and Franz Theuring for providing the IRES-LacZ-MC1-Neo cassette. This work was supported by the DFG: SFB 665/B3 to R.N., SFB 665/Z to C.B., and grant MH51699 (National Institutes of Health) to J.C. Bettina Holtmann, Elvira Rhode, Katja Becker, and Boris Jerchow are acknowledged for their help with embryonic stem cell work and blastocyst injection. T.T. and P.B. are fellows of the GRK 1123. S.W. is now at Molecular Cell Biology Group, Ruhr-Universität Bochum, 44801 Bochum, Germany, but work was performed in the lab of M.S. and was supported by the DFG: SFB 581/B1 and Z4 to M.S.
PY - 2009/9/18
Y1 - 2009/9/18
N2 - 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 LPA2 receptor-deficient animals, and uptake of phospholipids is reduced in PRG-1-deficient neurons, we assessed PRG-1/LPA2 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 LPA2 receptor signaling.
AB - 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 LPA2 receptor-deficient animals, and uptake of phospholipids is reduced in PRG-1-deficient neurons, we assessed PRG-1/LPA2 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 LPA2 receptor signaling.
KW - MOLNEURO
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U2 - 10.1016/j.cell.2009.06.050
DO - 10.1016/j.cell.2009.06.050
M3 - Article
C2 - 19766573
AN - SCOPUS:70149110413
SN - 0092-8674
VL - 138
SP - 1222
EP - 1235
JO - Cell
JF - Cell
IS - 6
ER -