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 ~5million 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 thisSNP. 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.
Highlights
Accurate synaptic transmission is a fundamental requirement for normal brain function (Turrigiano, 2011), and signaling alterations at the excitatory synapse have been related to psychiatric disorders such as schizophrenia (Harrison & Weinberger, 2005; Coyle, 2006; Belforte et al, 2010)
To understand the molecular consequences of the human single nucleotide polymorphism (SNP) resulting in arginine (R) to threonine (T) exchange at position 345 in the amino acid chain of plasticity-related gene 1 (PRG-1), we established HEK cell lines with stable expression of the mouse homolog of this SNP, PRG-1R346T, and found similar membrane localization when compared to wild-type PRG-1
After application of fluorescence labeled lysophosphatidic acid (LPA) (TopFluor (TF)-LPA) and removal of surface bound TF-LPA using 0.001% SDS, PRG-1R346Texpressing cells displayed a lower fluorescence signal in intracellular compartments (Fig 1B). This finding was quantified by FACS analysis revealing a significantly reduced capacity of PRG-1R346T-expressing cells to internalize TFLPA when compared to wild-type PRG-1 (wtPRG-1) (Fig 1D)
Summary
Accurate synaptic transmission is a fundamental requirement for normal brain function (Turrigiano, 2011), and signaling alterations at the excitatory synapse have been related to psychiatric disorders such as schizophrenia (Harrison & Weinberger, 2005; Coyle, 2006; Belforte et al, 2010). Recent research shows that bioactive lipid signaling and protein–lipid interaction play major roles in all steps of endo- and exocytosis processes, including synaptic vesicle cycling (Di Paolo et al, 2004). Plasticity-related gene 1 (PRG-1, assigned as LPPR4), a neuron-specific molecule in the brain, is an important postsynaptic control element of this pathway (Trimbuch et al, 2009). We demonstrated that the absence of PRG-1 (Brauer et al, 2003), which is involved in synaptic phospholipid signaling, leads to hippocampal hyperexcitability via increased glutamate release at the synapse (Trimbuch et al, 2009). A single nucleotide polymorphism (SNP, rs138327459, NHLBI Exome Sequencing Project https://esp.gs.washington.edu/drupal/) was detected in humans resulting in an arginine (R) to threonine (T) exchange at position 345 of the amino acid chain
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