Molecular cause and functional impact of altered synaptic lipid signaling due to a prg‐1 gene SNP

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 
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. 
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Author:Johannes Vogt, Jenq‐Wei Yang, Arian Mobascher, Jin Cheng, Yunbo Li, Xingfeng Liu, Jan Baumgart, Carine Thalman, Sergei Kirischuk, Petr Unichenko, Guilherme Horta, Konstantin Radyushkin, Albrecht Stroh, Sebastian Richers, Nassim Sahragard, Ute Distler, Stefan Tenzer, Lianyong Qiao, Klaus Lieb, Oliver Tüscher, Harald Binder, Nerea Ferreirós Bouzas, Irmgard Tegeder, Andrew J. Morris, Sergiu Gropa, Peter Nürnberg, Mohammad R. Toliat, Georg Winterer, Heiko J. Luhmann, Jisen Huai, Robert Nitsch
URN:urn:nbn:de:hebis:30:3-424704
DOI:http://dx.doi.org/10.15252/emmm.201505677
ISSN:1757-4684
ISSN:1757-4676
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=26671989
Parent Title (English):EMBO molecular medicine
Publisher:Wiley-VCH
Place of publication:Weinheim
Document Type:Article
Language:English
Date of Publication (online):2017/01/30
Date of first Publication:2015/12/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/01/30
Tag:PRG-1; bioactive phospholipids; cortical network; psychiatric disorders; synapse
Volume:8
Issue:1
Pagenumber:14
First Page:25
Last Page:38
Note:
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
HeBIS PPN:425293092
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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