Vogt, Johannes ORCID: 0000-0003-2439-8247, Yang, Jenq-Wei, Mobascher, Arian, Cheng, Jin, Li, Yunbo, Liu, Xingfeng, Baumgart, Jan ORCID: 0000-0003-1996-4267, Thalman, Carine, Kirischuk, Sergei, Unichenko, Petr, Horta, Guilherme, Radyushkin, Konstantin, Stroh, Albrecht, Richers, Sebastian, Sahragard, Nassim, Distler, Ute ORCID: 0000-0002-8031-6384, Tenzer, Stefan ORCID: 0000-0003-3034-0017, Qiao, Lianyong, Lieb, Klaus, Tuescher, Oliver, Binder, Harald ORCID: 0000-0002-5666-8662, Ferreiros, Nerea, Tegeder, Irmgard ORCID: 0000-0001-7524-8025, Morris, Andrew J., Gropa, Sergiu, Nuernberg, Peter, Toliat, Mohammad R., Winterer, Georg, Luhmann, Heiko J. ORCID: 0000-0002-7934-8661, Huai, Jisen and Nitsch, Robert (2016). Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP. EMBO Mol. Med., 8 (1). S. 25 - 39. HOBOKEN: WILEY. ISSN 1757-4684

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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 similar to 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Vogt, JohannesUNSPECIFIEDorcid.org/0000-0003-2439-8247UNSPECIFIED
Yang, Jenq-WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mobascher, ArianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheng, JinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunboUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, XingfengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumgart, JanUNSPECIFIEDorcid.org/0000-0003-1996-4267UNSPECIFIED
Thalman, CarineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirischuk, SergeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unichenko, PetrUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horta, GuilhermeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radyushkin, KonstantinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroh, AlbrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richers, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sahragard, NassimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Distler, UteUNSPECIFIEDorcid.org/0000-0002-8031-6384UNSPECIFIED
Tenzer, StefanUNSPECIFIEDorcid.org/0000-0003-3034-0017UNSPECIFIED
Qiao, LianyongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lieb, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuescher, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binder, HaraldUNSPECIFIEDorcid.org/0000-0002-5666-8662UNSPECIFIED
Ferreiros, NereaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tegeder, IrmgardUNSPECIFIEDorcid.org/0000-0001-7524-8025UNSPECIFIED
Morris, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gropa, SergiuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winterer, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luhmann, Heiko J.UNSPECIFIEDorcid.org/0000-0002-7934-8661UNSPECIFIED
Huai, JisenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nitsch, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-291727
DOI: 10.15252/emmm.201505677
Journal or Publication Title: EMBO Mol. Med.
Volume: 8
Number: 1
Page Range: S. 25 - 39
Date: 2016
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-PHOSPHORYLATION; O-GLCNACYLATION; SCHIZOPHRENIA; AUTOTAXIN; GLYCOSYLATION; MODEL; MODULATION; MECHANISMS; INHIBITOR; RESPONSESMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/29172

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