Final Report Summary - LIPSYD (Lipid Signaling at the Glutamatergic Synapse: Involvement in Brain Network Function and Psychiatric Disorders)
In addition to our studies to the role of LPA in psychiatric disorders we could show that 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 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 with 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. This data gives further support to our idea that intervention into bioactive lipid signaling is a promising strategy to interfere with glutamate-dependent symptoms in psychiatric diseases.
In ordert to further understand the role of PRG-1 in human cortical processing, we next performed a prospective study and analyzed PRG-1R345T monoallelic human carriers. Here, EEG-analysis revealed decreased theta power in the frontal cortex in a conditional stimulus paradigma and after transcranial magnetic stimulation (TMS). Moreover, resting-state EEG revealed increased gamma coherence between the temporal and the frontal cortex. These results were in line with our in-vivo field potential analyses in freely moving PRG-1 deficient mice. We therefore used the generated transgenic mouse line expressing this human mutation (PRG-1R346T in mice) and found in this mouse line several behavioral characteristics previously observed in PRG-1R346T mutation carriers (e.g. reduced PPI, an anxiety phenotype and a depressive-like behavior).
In sum our experimental data revealed a novel regulatory system at glutamatergic cortical synapses which acts via bioactive phospholipids. Moreover, we could show that intervention into synaptic lipid signaling might be a novel therapeutic strategy to tackle cortical hyperexcitability-related psychiatric disorders.