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001028963 1001_ $$0P:(DE-HGF)0$$aTüscher, Oliver$$b0$$eFirst author
001028963 245__ $$aAltered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders
001028963 260__ $$a[London]$$bSpringer Nature$$c2024
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001028963 520__ $$aExcitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.
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001028963 7001_ $$0P:(DE-HGF)0$$aMuthuraman, Muthuraman$$b1
001028963 7001_ $$0P:(DE-HGF)0$$aHorstmann, Johann-Philipp$$b2
001028963 7001_ $$0P:(DE-HGF)0$$aHorta, Guilherme$$b3
001028963 7001_ $$0P:(DE-HGF)0$$aRadyushkin, Konstantin$$b4
001028963 7001_ $$0P:(DE-HGF)0$$aBaumgart, Jan$$b5
001028963 7001_ $$0P:(DE-HGF)0$$aSigurdsson, Torfi$$b6
001028963 7001_ $$00000-0002-1012-4563$$aEndle, Heiko$$b7
001028963 7001_ $$0P:(DE-HGF)0$$aJi, Haichao$$b8
001028963 7001_ $$00000-0002-3890-9012$$aKuhnhäuser, Prisca$$b9
001028963 7001_ $$00000-0002-5416-7397$$aGötz, Jan$$b10
001028963 7001_ $$0P:(DE-HGF)0$$aKepser, Lara-Jane$$b11
001028963 7001_ $$00000-0003-4519-4956$$aLotze, Martin$$b12
001028963 7001_ $$0P:(DE-HGF)0$$aGrabe, Hans J.$$b13
001028963 7001_ $$0P:(DE-HGF)0$$aVölzke, Henry$$b14
001028963 7001_ $$00000-0002-9264-5003$$aLeehr, Elisabeth J.$$b15
001028963 7001_ $$0P:(DE-HGF)0$$aMeinert, Susanne$$b16
001028963 7001_ $$00000-0003-4749-3298$$aOpel, Nils$$b17
001028963 7001_ $$0P:(DE-HGF)0$$aRichers, Sebastian$$b18
001028963 7001_ $$00000-0001-9410-4086$$aStroh, Albrecht$$b19
001028963 7001_ $$0P:(DE-Juel1)162297$$aDaun, Silvia$$b20$$ufzj
001028963 7001_ $$00000-0001-5072-2149$$aTittgemeyer, Marc$$b21
001028963 7001_ $$0P:(DE-HGF)0$$aUphaus, Timo$$b22
001028963 7001_ $$00000-0003-3708-8600$$aSteffen, Falk$$b23
001028963 7001_ $$00000-0002-1231-1928$$aZipp, Frauke$$b24
001028963 7001_ $$0P:(DE-HGF)0$$aGroß, Joachim$$b25
001028963 7001_ $$00000-0002-2551-5655$$aGroppa, Sergiu$$b26
001028963 7001_ $$0P:(DE-HGF)0$$aDannlowski, Udo$$b27
001028963 7001_ $$0P:(DE-HGF)0$$aNitsch, Robert$$b28
001028963 7001_ $$00000-0003-2439-8247$$aVogt, Johannes$$b29$$eCorresponding author
001028963 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-024-02598-2$$gVol. 29, no. 11, p. 3537 - 3552$$n11$$p3537 - 3552$$tMolecular psychiatry$$v29$$x1359-4184$$y2024
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