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EMBO Mol Med. 2016 Jan 1;8(1):25-38. doi: 10.15252/emmm.201505677.

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

Author information

1
Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany johannes.vogt@unimedizin-mainz.de robert.nitsch@unimedizin-mainz.de.
2
Institute for Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
3
Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
4
Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
5
Focus Program Translational Neuroscience (FTN), University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
6
Focus Program Translational Neuroscience (FTN), University Medical Center, Johannes Gutenberg-University, Mainz, Germany Institute for Immunology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
7
Institute for Immunology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
8
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
9
Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
10
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA.
11
Department of Neurology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
12
Cologne Center for Genomics (CCG), University of Cologne, Cologne, 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.

KEYWORDS:

PRG‐1; bioactive phospholipids; cortical network; psychiatric disorders; synapse

PMID:
26671989
PMCID:
PMC4718157
DOI:
10.15252/emmm.201505677
[Indexed for MEDLINE]
Free PMC Article

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