Authors

Johannes Vogt, Johannes Gutenberg‐University, Germany
Jenq-Wei Yang, Johannes Gutenberg‐University, Germany
Arian Mobascher, Johannes Gutenberg‐University, Germany
Jin Cheng, Johannes Gutenberg‐University, Germany
Yunbo Li, Johannes Gutenberg‐University, Germany
Xingfeng Liu, Johannes Gutenberg‐University, Germany
Jan Baumgart, Johannes Gutenberg‐University, Germany
Carine Thalman, Johannes Gutenberg‐University, Germany
Sergei Kirischuk, Johannes Gutenberg‐University, Germany
Petr Unichenko, Johannes Gutenberg‐University, Germany
Guilherme Horta, Johannes Gutenberg‐University, Germany
Konstantin Radyushkin, Johannes Gutenberg‐University, Germany
Albrecht Stroh, Johannes Gutenberg‐University, Germany
Sebastian Richers, Johannes Gutenberg‐University, Germany
Nassim Sahragard, Johannes Gutenberg‐University, Germany
Ute Distler, Johannes Gutenberg‐University, Germany
Stefan Tenzer, Johannes Gutenberg‐University, Germany
Lianyong Qiao, Johannes Gutenberg‐University, Germany
Klaus Lieb, Johannes Gutenberg‐University, Germany
Oliver Tüscher, Johannes Gutenberg‐University, Germany
Harald Binder, Johannes Gutenberg‐University, Germany
Nerea Ferreiros, Goethe‐University Hospital, Germany
Irmgard Tegeder, Goethe‐University Hospital, Germany
Andrew J. Morris, University of KentuckyFollow
Sergiu Gropa, Johannes Gutenberg‐University, Germany
Peter Nürnberg, University of Cologne, Germany
Mohammad R. Toliat, University of Cologne, Germany
Georg Winterer, University of Cologne, Germany
Heiko J. Luhmann, Johannes Gutenberg‐University, Germany
Jisen Huai, Johannes Gutenberg‐University, Germany
Robert Nitsch, Johannes Gutenberg‐University, Germany

Abstract

Loss of plasticity‐related gene 1 (PRG‐1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg‐1 (R345T/mutPRG‐1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss‐of‐PRG‐1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG‐1+/− mice, which are animal correlates of human PRG‐1+/mut carriers, showed an altered cortical network function and stress‐related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA‐synthesizing molecule autotaxin. In line, EEG recordings in a human population‐based cohort revealed an E/I balance shift in monoallelic mutPRG‐1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress‐related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate‐dependent symptoms in psychiatric diseases.

Document Type

Article

Publication Date

1-2016

Notes/Citation Information

Published in EMBO Molecular Medicine, v. 8, no. 1, p. 25-38.

© 2015 The Authors.

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Digital Object Identifier (DOI)

http://dx.doi.org/10.15252/emmm.201505677

Funding Information

The studies were funded by the European Research Council (ERC-AG “LiPsyD”) and the Deutsche Forschungsgemeinschaft (DFG) within the CRC1080 (to RN, JV, IT, JH, HJL, and AS).

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