TY - JOUR
T1 - GRK3 deficiency elicits brain immune activation and psychosis
AU - Sellgren, Carl M.
AU - Imbeault, Sophie
AU - Larsson, Markus K.
AU - Oliveros, Alfredo
AU - Nilsson, Ida A.K.
AU - Codeluppi, Simone
AU - Orhan, Funda
AU - Bhat, Maria
AU - Tufvesson-Alm, Maximilian
AU - Gracias, Jessica
AU - Kegel, Magdalena E.
AU - Zheng, Yiran
AU - Faka, Anthi
AU - Svedberg, Marie
AU - Powell, Susan B.
AU - Caldwell, Sorana
AU - Kamenski, Mary E.
AU - Vawter, Marquis P.
AU - Schulmann, Anton
AU - Goiny, Michel
AU - Svensson, Camilla I.
AU - Hökfelt, Tomas
AU - Schalling, Martin
AU - Schwieler, Lilly
AU - Cervenka, Simon
AU - Choi, Doo Sup
AU - Landén, Mikael
AU - Engberg, Göran
AU - Erhardt, Sophie
N1 - Funding Information:
Acknowledgements We are grateful to the staff of Affektivt Centrum, Norra Stockholms Psykiatri, and at the Department of Physiology and Pharmacology at Karolinska Institutet for technical assistance. We also thank Dr. Leandro Agudelo and Paula da Silva from the laboratory of Dr. Jorge Ruas for assistance with qPCR. This work was supported by grants from the Swedish Research Council (ML 2018-02653, GE 2019-01452, SE 2017-00875, CS 2009-3068, CSM 2017-02559), the Swedish Foundation for Strategic Research (KF10-0039; ML), The KI-AstraZeneca Joint Research Program (SE), Torsten Söderbergs Stiftelse (SE), the Swedish Brain Foundation (SE, GE), Petrus och Augusta Hedlunds Stiftelse (SE), Märta Lundqvists Stiftelse (SE), Åhlén-stiftelsen (GE), National Institute of Mental Health (R01MH091407 (SB)), the Stanley Medical Research Institute (ML), the regional agreement on medical training and clinical research between Stockholm County Council (ALF 20170019; ML) and the Karolinska Institutet (KID (SE and LS)); the Broad Institute (ML), Knut och Alice Wallenbergs Stiftelse (CSM), the Mayo Clinic-Karolinska Institutet Collaborative Grant Foundation (SE and DSC), and the Mayo Clinic Metabolomics Core Pilot Grant (DSC and SE). No funding sources had any role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11
Y1 - 2021/11
N2 - The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3−/− mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3−/− mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.
AB - The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3−/− mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3−/− mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.
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U2 - 10.1038/s41380-021-01106-0
DO - 10.1038/s41380-021-01106-0
M3 - Article
C2 - 33976392
AN - SCOPUS:85105783802
SN - 1359-4184
VL - 26
SP - 6820
EP - 6832
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -