TY  - JOUR
A1  - Vogt, Johannes
A1  - Yang, Jenq‐Wei
A1  - Mobascher, Arian
A1  - Cheng, Jin
A1  - Li, Yunbo
A1  - Liu, Xingfeng
A1  - Baumgart, Jan
A1  - Thalman, Carine
A1  - Kirischuk, Sergei
A1  - Unichenko, Petr
A1  - Horta, Guilherme
A1  - Radyushkin, Konstantin
A1  - Stroh, Albrecht
A1  - Richers, Sebastian
A1  - Sahragard, Nassim
A1  - Distler, Ute
A1  - Tenzer, Stefan
A1  - Qiao, Lianyong
A1  - Lieb, Klaus
A1  - Tüscher, Oliver
A1  - Binder, Harald
A1  - Ferreirós Bouzas, Nerea
A1  - Tegeder, Irmgard
A1  - Morris, Andrew J.
A1  - Gropa, Sergiu
A1  - Nürnberg, Peter
A1  - Toliat, Mohammad Reza
A1  - Winterer, Georg
A1  - Luhmann, Heiko J.
A1  - Huai, Jisen
A1  - Nitsch, Robert
T1  - Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP
T2  - EMBO molecular medicine
N2  - 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.
KW  - bioactive phospholipids
KW  - cortical network
KW  - PRG-1
KW  - psychiatric disorders
KW  - synapse
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42470
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-424704
SN  - 1757-4684
SN  - 1757-4676
N1  - License: 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
VL  - 8
IS  - 1
SP  - 25
EP  - 38
PB  - Wiley-VCH
CY  - Weinheim
ER  -