Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders

Carine Thalman, Guilherme Horta, Lianyong Qiao, Heiko Endle, Irmgard Tegeder, Hong Cheng, Gregor Laube, Torfi Sigrudsson, Maria Jelena Hauser, Stefan Tenzer, Ute Distler, Junken Aoki, Andrew J. Morris, Gerd Geisslinger, Jochen Röper, Sergei Kirischuk, Heiko J. Luhmann, Konstantin Radyushkin, Robert Nitsch, Johannes Vogt

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9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1699-1710
Number of pages12
JournalMolecular psychiatry
Volume23
Issue number8
DOIs
Publication statusPublished - 2018 Aug 1

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Thalman, C., Horta, G., Qiao, L., Endle, H., Tegeder, I., Cheng, H., Laube, G., Sigrudsson, T., Hauser, M. J., Tenzer, S., Distler, U., Aoki, J., Morris, A. J., Geisslinger, G., Röper, J., Kirischuk, S., Luhmann, H. J., Radyushkin, K., Nitsch, R., & Vogt, J. (2018). Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders. Molecular psychiatry, 23(8), 1699-1710. https://doi.org/10.1038/s41380-018-0053-1