title: 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.
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany johannes.vogt@unimedizin-mainz.de robert.nitsch@unimedizin-mainz.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogt
authors.affiliation: Institute for Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Jenq-Wei
authors.initials: JW
authors.lastname: Yang
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Arian
authors.initials: A
authors.lastname: Mobascher
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Xingfeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Baumgart
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Carine
authors.initials: C
authors.lastname: Thalman
authors.affiliation: Institute for Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Sergei
authors.initials: S
authors.lastname: Kirischuk
authors.affiliation: Institute for Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Petr
authors.initials: P
authors.lastname: Unichenko
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Horta
authors.affiliation: Focus Program Translational Neuroscience (FTN), University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Radyushkin
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stroh
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Richers
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Nassim
authors.initials: N
authors.lastname: Sahragard
authors.affiliation: 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.
authors.forename: Ute
authors.initials: U
authors.lastname: Distler
authors.affiliation: Institute for Immunology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Lianyong
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Lieb
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Tüscher
authors.affiliation: Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Binder
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Department of Neurology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Sergiu
authors.initials: S
authors.lastname: Gropa
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Winterer
authors.affiliation: Institute for Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Luhmann
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Jisen
authors.initials: J
authors.lastname: Huai
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany johannes.vogt@unimedizin-mainz.de robert.nitsch@unimedizin-mainz.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
mesh_terms: D000818:Animals; D004569:Electroencephalography; D005071:Evoked Potentials; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D001523:Mental Disorders / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010748:Phosphopeptides / Q000032:analysis; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013003:Somatosensory Cortex / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D008246:Lysophospholipids; D010748:Phosphopeptides; D010727:Phosphoric Diester Hydrolases; D011509:Proteoglycans; D033921:Vesicular Transport Proteins; D000099189:Lysophospholipase D; C075430:serglycin; C032881:lysophosphatidic acid
keywords: PRG‐1; bioactive phospholipids; cortical network; psychiatric disorders; synapse