TY  - JOUR
AU  - Gaebler, Arnim J.
AU  - Fakour, Nilüfer
AU  - Stöhr, Felix
AU  - Zweerings, Jana
AU  - Taebi, Arezoo
AU  - Suslova, Mariia
AU  - Dukart, Jürgen
AU  - Hipp, Joerg F.
AU  - Adhikari, Bhim M.
AU  - Kochunov, Peter
AU  - Muthukumaraswamy, Suresh D.
AU  - Forsyth, Anna
AU  - Eggermann, Thomas
AU  - Kraft, Florian
AU  - Kurth, Ingo
AU  - Paulzen, Michael
AU  - Gründer, Gerhard
AU  - Schneider, Frank
AU  - Mathiak, Klaus
TI  - Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI
JO  - Translational Psychiatry
VL  - 13
IS  - 1
SN  - 2158-3188
CY  - London
PB  - Nature Publishing Group
M1  - FZJ-2023-04973
SP  - 59
PY  - 2023
AB  - Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.
LB  - PUB:(DE-HGF)16
C6  - 36797233
UR  - <Go to ISI:>//WOS:000935891400001
DO  - DOI:10.1038/s41398-023-02344-2
UR  - https://juser.fz-juelich.de/record/1018679
ER  -