Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders

  • 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 lowerExcitation/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.show moreshow less

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Metadaten
Author:Oliver Tüscher, Muthuraman MuthuramanORCiDGND, Johann-Philipp Horstmann, Guilherme Horta, Konstantin Radyushkin, Jan Baumgart, Torfi Sigurdsson, Heiko Endle, Haichao Ji, Prisca Kuhnhäuser, Jan Götz, Lara-Jane Kepser, Martin Lotze, Hans J. Grabe, Henry Völzke, Elisabeth J. Leehr, Susanne Meinert, Nils Opel, Sebastian Richers, Albrecht Stroh, Silvia Daun, Marc Tittgemeyer, Timo Uphaus, Falk Steffen, Frauke Zipp, Joachim Groß, Sergiu Groppa, Udo Dannlowski, Robert Nitsch, Johannes Vogt
Frontdoor URLhttps://opus.bibliothek.uni-augsburg.de/opus4/113436
ISSN:1359-4184OPAC
ISSN:1476-5578OPAC
Parent Title (English):Molecular Psychiatry
Publisher:Springer Science and Business Media LLC
Type:Article
Language:English
Year of first Publication:2024
Publishing Institution:Universität Augsburg
Release Date:2024/06/12
DOI:https://doi.org/10.1038/s41380-024-02598-2
Institutes:Fakultät für Angewandte Informatik
Fakultät für Angewandte Informatik / Institut für Informatik
Fakultät für Angewandte Informatik / Institut für Informatik / Professur für Informatik in der Medizintechnik
Dewey Decimal Classification:0 Informatik, Informationswissenschaft, allgemeine Werke / 00 Informatik, Wissen, Systeme / 004 Datenverarbeitung; Informatik
Latest Publications (not yet published in print):Aktuelle Publikationen (noch nicht gedruckt erschienen)
Licence (German):CC-BY 4.0: Creative Commons: Namensnennung (mit Print on Demand)