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@ARTICLE{Tscher:1028963,
author = {Tüscher, Oliver and Muthuraman, Muthuraman and Horstmann,
Johann-Philipp and Horta, Guilherme and Radyushkin,
Konstantin and Baumgart, Jan and Sigurdsson, Torfi and
Endle, Heiko and Ji, Haichao and Kuhnhäuser, Prisca and
Götz, Jan and Kepser, Lara-Jane and Lotze, Martin and
Grabe, Hans J. and Völzke, Henry and Leehr, Elisabeth J.
and Meinert, Susanne and Opel, Nils and Richers, Sebastian
and Stroh, Albrecht and Daun, Silvia and Tittgemeyer, Marc
and Uphaus, Timo and Steffen, Falk and Zipp, Frauke and
Groß, Joachim and Groppa, Sergiu and Dannlowski, Udo and
Nitsch, Robert and Vogt, Johannes},
title = {{A}ltered cortical synaptic lipid signaling leads to
intermediate phenotypes of mental disorders},
journal = {Molecular psychiatry},
volume = {29},
number = {11},
issn = {1359-4184},
address = {[London]},
publisher = {Springer Nature},
reportid = {FZJ-2024-04900},
pages = {3537 - 3552},
year = {2024},
abstract = {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.},
cin = {INM-3},
ddc = {610},
cid = {I:(DE-Juel1)INM-3-20090406},
pnm = {5251 - Multilevel Brain Organization and Variability
(POF4-525) / DFG project G:(GEPRIS)431549029 - SFB 1451:
Schlüsselmechanismen normaler und krankheitsbedingt
gestörter motorischer Kontrolle (431549029)},
pid = {G:(DE-HGF)POF4-5251 / G:(GEPRIS)431549029},
typ = {PUB:(DE-HGF)16},
pubmed = {38806692},
UT = {WOS:001234275100002},
doi = {10.1038/s41380-024-02598-2},
url = {https://juser.fz-juelich.de/record/1028963},
}