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

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.

SUBMITTER: Vogt J

PROVIDER: S-EPMC4718157 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Vogt Johannes J Yang Jenq-Wei JW Mobascher Arian A Cheng Jin J Li Yunbo Y Liu Xingfeng X Baumgart Jan J Thalman Carine C Kirischuk Sergei S Unichenko Petr P Horta Guilherme G Radyushkin Konstantin K Stroh Albrecht A Richers Sebastian S Sahragard Nassim N Distler Ute U Tenzer Stefan S Qiao Lianyong L Lieb Klaus K Tüscher Oliver O Binder Harald H Ferreiros Nerea N Tegeder Irmgard I Morris Andrew J AJ Gropa Sergiu S Nürnberg Peter P Toliat Mohammad R MR Winterer Georg G Luhmann Heiko J HJ Huai Jisen J Nitsch Robert R

EMBO molecular medicine 20160101 1

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 cell ...[more]

PMID: 26671989

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

Publications

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

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