We have recently shown that synaptic phospholipids are novel players in the regulation of glutamatergic transmission and cortical network excitability. Our data suggest that bioactive phospholipids such as lysophosphatidic acids (LPA) play an important regulatory role in synaptic neurotransmission and plasticity. LPA is a short-lived, but potent signaling molecule acting via specific G-protein coupled receptors, LPA-R1-6. LPA-levels are tightly regulated by specific phosphatases (LPP1-3) in the perisynaptic space as well as by plasticity-related gene 1 (PRG-1/LPPR4) in the synaptic cleft suggesting that LPA synthesis and action are locally restricted. LPA is a powerful modulator of presynaptic glutamate release by activation of presynaptic LPAR2 receptors, which regulate glutamate release probability. In cortical networks, LPA regulates the cortical excitation-inhibition (E/I) balance and controls cortical sensory information processing in mice and humans.
Our data suggest that alterations in E/I-balance and in pre-attentive stimulus processing, which are considered biomarkers/endophenotypes of psychiatric disorders result from a reduced PRG-1 action at the synapse, leading to increased LPA-levels and loss of proper cortical network function. Analysis of human subjects led to identification of a loss-of-function PRG-1 variant (PRG-1R345T) which affects 0,6% of western population. Human subjects expressing this variant displayed higher cortical excitability, increased synchrony in brain rhythms and a deficit in pre-attentive stimulus processing (P50 wave described in Vogt et al., 2016).
In addition to the above described symptom, transgenic animals with targeted alterations in synaptic lipid signalling display deficits in memory formation, altered adult neurogenesis and behavioural changes associated with mood disorders, which were partially detected in human PRG-1R345T expressing subjects. Moreover, we could show that synaptic lipid mediated signalling is involved in age-related cortical hyperexcitability, which is a hallmark of neurodegenerative disorders (Fischer et al., 2021).
These data suggest that cortical excitation/inhibition imbalances contribute to glutamate-related electrophysiological, cellular changes and behavioral abnormalities in psychiatric disorders (e.g., the glutamate hypothesis of schizophrenia) and show that, in addition to the known NMDA receptor hypofunction on inhibitory neurons, alteration of glutamatergic activity on excitatory neurons may contribute to psychiatric diseases including age-related disorders.
Regional changes in cortical E/I-balance have been recognized to be important factors in psychiatric disorders including Schizophrenia, Autism and mood disorders. Synaptic lipids are novel factors shown to regulate glutamatergic transmission and thereby cortical E/I-balance. However, beside changes on the molecular and on the electrophysiological level, synaptic lipids lead to cellular changes as present in adult neurogenesis. Our data suggest that targeted modulation of synaptic lipid signalling bear the potential for a novel therapeutic option for glutamate-regulated psychiatric and neurodegenerative disorders.
Department of Molecular and Translational Neuroscience | Institute II of Anatomy
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