TY  - JOUR
A1  - Thalman, Carine
A1  - Horta, Guilherme
A1  - Qiao, Lianyong
A1  - Endle, Heiko
A1  - Tegeder, Irmgard
A1  - Cheng, Hong
A1  - Laube, Gregor
A1  - Sigurdsson, Torfi
A1  - Hauser, Maria Jelena
A1  - Tenzer, Stefan
A1  - Distler, Ute
A1  - Aoki, Junken
A1  - Morris, Andrew J.
A1  - Geisslinger, Gerd
A1  - Röper, Jochen
A1  - Kirischuk, Sergei
A1  - Luhmann, Heiko
A1  - Radyushkin, Konstantin
A1  - Nitsch, Robert
A1  - Vogt, Johannes
T1  - Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders
T2  - Molecular psychiatry
N2  - 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.
KW  - Neuroscience
KW  - Schizophrenia
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50851
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-508511
SN  - 1476-5578
SN  - 1359-4184
N1  - Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
N1  - Correction erschienen in: Molecular psychiatry, 24.2019, doi:10.1038/s41380-018-0320-1
VL  - 23
IS  - 8
SP  - 1699
EP  - 1710
PB  - Macmillan
CY  - London
ER  -