TY - JOUR
T1 - Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP
AU - Vogt, Johannes
AU - Yang, Jenq Wei
AU - Mobascher, Arian
AU - Cheng, Jin
AU - Li, Yunbo
AU - Liu, Xingfeng
AU - Baumgart, Jan
AU - Thalman, Carine
AU - Kirischuk, Sergei
AU - Unichenko, Petr
AU - Horta, Guilherme
AU - Radyushkin, Konstantin
AU - Stroh, Albrecht
AU - Richers, Sebastian
AU - Sahragard, Nassim
AU - Distler, Ute
AU - Tenzer, Stefan
AU - Qiao, Lianyong
AU - Lieb, Klaus
AU - Tüscher, Oliver
AU - Binder, Harald
AU - Ferreiros, Nerea
AU - Tegeder, Irmgard
AU - Morris, Andrew J.
AU - Gropa, Sergiu
AU - Nürnberg, Peter
AU - Toliat, Mohammad R.
AU - Winterer, Georg
AU - Luhmann, Heiko J.
AU - Huai, Jisen
AU - Nitsch, Robert
N1 - Publisher Copyright:
© 2016 EMBO.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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. Synopsis: Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG-1. A common loss-of-function SNP in PRG-1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG-1 SNP (R345T), present in a monoallelic variant, abolished PRG-1 function by impeding its ability for LPA internalization due to altered glycosylation. Monoallelic PRG-1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress-related behaviors, an endophenotype of psychiatric disorders. Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild-type levels, opening a new therapeutic perspective for stress-related mental dysfunctions. Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG-1. A common loss-of-function SNP in PRG-1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders.
AB - 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. Synopsis: Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG-1. A common loss-of-function SNP in PRG-1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders. The human PRG-1 SNP (R345T), present in a monoallelic variant, abolished PRG-1 function by impeding its ability for LPA internalization due to altered glycosylation. Monoallelic PRG-1 deficiency affected cortical information processing, leading to decreased somatosensory filter function in rodents and humans, and impaired resilience during stress-related behaviors, an endophenotype of psychiatric disorders. Pharmacological intervention specifically targeting phospholipid signaling rescued cortical somatosensory filter function to wild-type levels, opening a new therapeutic perspective for stress-related mental dysfunctions. Synaptic phospholipids are potent bioactive factors known to increase glutamatergic transmission in excitatory neurons, and they are normally cleared from the synaptic cleft by PRG-1. A common loss-of-function SNP in PRG-1 affects the pathophysiology and behavior in a way reminiscent of psychiatric disorders.
KW - Bioactive phospholipids
KW - Cortical network
KW - PRG-1
KW - Psychiatric disorders
KW - Synapse
UR - http://www.scopus.com/inward/record.url?scp=84956715288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84956715288&partnerID=8YFLogxK
U2 - 10.15252/emmm.201505677
DO - 10.15252/emmm.201505677
M3 - Article
C2 - 26671989
AN - SCOPUS:84956715288
SN - 1757-4676
VL - 8
SP - 25
EP - 38
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
ER -