Journal Article

FZJ-2024-04900

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders

Tüscher, O. (First author) ; Muthuraman, M. ; Horstmann, J.-P. ; Horta, G. ; Radyushkin, K. ; Baumgart, J. ; Sigurdsson, T. ; Endle, H. ; Ji, H. ; Kuhnhäuser, P. ; Götz, J. ; Kepser, L.-J. ; Lotze, M. ; Grabe, H. J. ; Völzke, H. ; Leehr, E. J. ; Meinert, S. ; Opel, N. ; Richers, S. ; Stroh, A. ; Daun, S.FZJ* ; Tittgemeyer, M. ; Uphaus, T. ; Steffen, F. ; Zipp, F. ; Groß, J. ; Groppa, S. ; Dannlowski, U. ; Nitsch, R. ; Vogt, J. (Corresponding author)

2024
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41380-024-02598-2  doi:10.34734/FZJ-2024-04900

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.

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Contributing Institute(s):

1. Kognitive Neurowissenschaften (INM-3)

Research Program(s):

1. 5251 - Multilevel Brain Organization and Variability (POF4-525) (POF4-525)
2. DFG project G:(GEPRIS)431549029 - SFB 1451: Schlüsselmechanismen normaler und krankheitsbedingt gestörter motorischer Kontrolle (431549029) (431549029)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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