Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.
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This work was supported by the Deutsche Forschungsgemeinschaft (SFB 1080 and 1193) to JV, RN, IT, JR, TS, KR and HJL, by the European Research Council (ERC-AG “LiPsyD” to RN) and by the Boehringer-Ingelheim Foundation to JV.
The online version of this article (https://doi.org/10.1038/s41380-018-0053-1) contains supplementary material, which is available to authorized users.
Thalman, Carine; Horta, Guilherme; Qiao, Lianyong; Endle, Heiko; Tegeder, Irmgard; Cheng, Hong; Laube, Gregor; Sigurdsson, Torfi; Hauser, Maria Jelena; Tenzer, Stefan; Distler, Ute; Aoki, Junken; Morris, Andrew J.; Geisslinger, Gerd; Röper, Jochen; Kirischuk, Sergei; Luhmann, Heiko J.; Radyushkin, Konstantin; Nitsch, Robert; and Vogt, Johannes, "Synaptic Phospholipids as a New Target for Cortical Hyperexcitability and E/I Balance in Psychiatric Disorders" (2018). Internal Medicine Faculty Publications. 152.