TY  - JOUR
AU  - Tüscher, Oliver
AU  - Muthuraman, Muthuraman
AU  - Horstmann, Johann-Philipp
AU  - Horta, Guilherme
AU  - Radyushkin, Konstantin
AU  - Baumgart, Jan
AU  - Sigurdsson, Torfi
AU  - Endle, Heiko
AU  - Ji, Haichao
AU  - Kuhnhäuser, Prisca
AU  - Götz, Jan
AU  - Kepser, Lara-Jane
AU  - Lotze, Martin
AU  - Grabe, Hans J.
AU  - Völzke, Henry
AU  - Leehr, Elisabeth J.
AU  - Meinert, Susanne
AU  - Opel, Nils
AU  - Richers, Sebastian
AU  - Stroh, Albrecht
AU  - Daun, Silvia
AU  - Tittgemeyer, Marc
AU  - Uphaus, Timo
AU  - Steffen, Falk
AU  - Zipp, Frauke
AU  - Groß, Joachim
AU  - Groppa, Sergiu
AU  - Dannlowski, Udo
AU  - Nitsch, Robert
AU  - Vogt, Johannes
TI  - Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders
JO  - Molecular psychiatry
VL  - 29
IS  - 11
SN  - 1359-4184
CY  - [London]
PB  - Springer Nature
M1  - FZJ-2024-04900
SP  - 3537 - 3552
PY  - 2024
AB  - Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.
LB  - PUB:(DE-HGF)16
C6  - 38806692
UR  - <Go to ISI:>//WOS:001234275100002
DO  - DOI:10.1038/s41380-024-02598-2
UR  - https://juser.fz-juelich.de/record/1028963
ER  -