GRK3 deficiency elicits brain immune activation and psychosis

• Published in: Molecular psychiatry Vol. 26; no. 11; pp. 6820 - 6832
• Main Authors: Sellgren, Carl M., Imbeault, Sophie, Larsson, Markus K., Oliveros, Alfredo, Nilsson, Ida A. K., Codeluppi, Simone, Orhan, Funda, Bhat, Maria, Tufvesson-Alm, Maximilian, Gracias, Jessica, Kegel, Magdalena E., Zheng, Yiran, Faka, Anthi, Svedberg, Marie, Powell, Susan B., Caldwell, Sorana, Kamenski, Mary E., Vawter, Marquis P., Schulmann, Anton, Goiny, Michel, Svensson, Camilla I., Hökfelt, Tomas, Schalling, Martin, Schwieler, Lilly, Cervenka, Simon, Choi, Doo-Sup, Landén, Mikael, Engberg, Göran, Erhardt, Sophie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2021; Nature Publishing Group
• Subjects: 101/58; 13/1; 13/21; 13/51; 38/43; 631/378; 64/60; 692/699/476/1799; Amphetamines; Animals; b-Adrenergic-receptor kinase; Behavioral Sciences; Biochemistry & Molecular Biology; Biological Psychology; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Brain - metabolism; Brain research; Cell receptors; Cerebrospinal fluid; coupled receptor kinases; Development and progression; disruption; G protein-coupled receptor kinase; gene; Genetic aspects; Health aspects; IL-1β; Immune response; Immunomodulation; Kinases; Kynurenic acid; Kynurenic Acid - metabolism; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mental disorders; Mesencephalon; Mice; Neuroimaging; Neurosciences; Neurosciences & Neurology; Neurotransmission; Neurovetenskaper; p2x7; pathway; Pharmacotherapy; Phenotypes; Prefrontal cortex; promoter; Protein kinases; Proteins; Psychiatry; Psychoses; Psychosis; Psychotic Disorders - genetics; Psychotic Disorders - metabolism; Psykiatri; receptor; Schizophrenia; Schizophrenia - metabolism; Sweden
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-021-01106-0

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.